Combinations of vepdegestrant and CDK4 / 6 inhibitors for treating ESR1-mutant breast cancer

Abstract

Disclosed herein are methods for treating cancer (e.g., breast cancer such as ESR1-mutant breast cancer) comprising administering to a subject a daily dose of Compound A, or a pharmaceutically acceptable salt thereof, in combination with a CDK4 / 6 inhibitor such as abemaciclib or ribociclib.

Description

Attorney Docket No.: 100C-401885-WO ARVN0205W02COMBINATIONS OF ESTROGEN RECEPTOR DEGRADERS AND CDK4 / 6 INHIBITORSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 729,866, filed December 9, 2024, the content of which is incorporated herein by reference in its entirety.BACKGROUND

[0002] In the United States, breast cancer is the second leading cause of cancer death in women. One in eight women in the United States will be diagnosed with breast cancer in her lifetime. In 2024, an estimated 310,720 women and 2,800 men will be diagnosed with invasive breast cancer. Accordingly, there is a need for new therapeutic methods that are useful in treating breast cancer.

[0003] Certain bifunctional compounds target specific cellular proteins for degradation via the ubiquitin-proteasome system. Examples of such proteolysis targeting chimeric compounds (i.e., “PROTAC protein degraders”) that target the Estrogen Receptor (ER) for ubiquitination and subsequent degradation are disclosed in International Publication No. WO 2018 / 102725, which is incorporated herein by reference in its entirety. Such bifunctional molecules exhibit a range of pharmacological activities consistent with the degradation of the ER including, but not limited to, treatment or amelioration of a disease condition such as cancer (e.g., breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer), or endometriosis.

[0004] A bifunctional molecule of particular interest is vepdegestrant (i.e., (S)-3-(5-(4-((l-(4- (( 1 R,2S)-6-hydroxy-2-phenyl- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (referred to herein as “Compound A”)), which has the molecular formula of C45H49N5O4 and the following structure:

[0005] Compound A is under development as a PROTAC protein degrader that targets estrogen receptor (ER) for the potential treatment of breast cancer and has been shown to be a useful modulator of targeted protein ubiquitination and degradation via the ubiquitin-proteasome pathway.SUMMARY

[0006] Provided are new therapeutic methods for treating breast cancer. In particular, the method disclosed herein can be useful in treating ESRI -mutant breast cancer. The ESRI gene encodes theAttorney Docket No.: 100C-401885-WO ARVN0205W02 estrogen receptor alpha, a nuclear hormone receptor activated by estrogen. Estrogen receptor alpha is crucial in regulating gene expression related to cell growth and differentiation in breast tissue. While ESRI mutation are rare in primary, treatment-naive breast tumors, they are more common in metastatic, hormone receptor-positive breast cancers, especially after endocrine therapy.

[0007] Vepdegestrant (i.e., (S)-3-(5-(4-((l-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen- 1 -yl)phenyl)piperidin-4-yl)methyl)piperazin- 1 -yl)- 1 -oxoisoindolin-2- yl)piperidine-2, 6-dione (referred to herein as “Compound A”)):(Compound A) is under development as a PROTAC protein degrader that targets estrogen receptor (ER) for the potential treatment of breast cancer and has been shown to be a useful modulator of targeted protein ubiquitination and degradation via the ubiquitin-proteasome pathway.

[0008] Compound A and pharmaceutically acceptable salts thereof are disclosed in International Publication Nos. WO 2018 / 102725 and WO 2021 / 041348; in U.S. Patent Nos. 10,647,698, 10,899,742, 11,104,666, and 12,162,859; and in U.S. Publication Nos. US 20220193072 and US 20230069491. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0009] The present disclosure, in some embodiments, provides a method for treating ESRI -mutant breast cancer comprising administering to a subject in need thereof a daily dose of Compound A:(Compound A), or a pharmaceutically acceptable salt thereof, in combination with abemaciclib or ribociclib, or a pharmaceutically acceptable salt of each thereof.

[0010] The disclosure also provides compositions, including pharmaceutical compositions, kits that include the compounds, and methods of using (or administering) the compounds.Attorney Docket No.: 100C-401885-WOARVN0205W02BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 shows antitumor effects of vepdegestrant in combination with abemaciclib or ribociclib in a CDK4 / 6 inhibitor-resistant ESRI Y537S-mutant PDX model. *P<0.05 at day 30 compared with vepdegestrant alone (t-test).

[0012] FIG. 2 shows antitumor activity (best percentage change from baseline in sum of target lesions) in response-evaluable patients (n=15). PD=progressive disease; PR=partial response; and SD=stable disease.

[0013] FIG. 3 shows treatment duration of the study.DETAILED DESCRIPTION

[0014] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.Definitions

[0015] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0016] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise.

[0017] As used herein, terms, including, but not limited to, “agent,” “composition,” “compound,” “drug,” and “therapeutic agent” may be used interchangeably to refer to compounds included in the methods and uses of the present disclosure.

[0018] As used herein, the terms, “subject” and “patient,” may be used interchangeably, to refer to any animal, including mammals. Mammals according to the disclosure include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans, and the like, and encompass mammals in utero. In embodiments, humans are suitable subjects. Human subjects may be of any gender and at any stage of development.

[0019] “Compound A” refers to vepdegestrant (i.e., (S)-3-(5-(4-((l-(4-((lR,2S)-6-hydroxy-2-phenyl- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)phenyl)piperidin-4-yl)methyl)piperazin- 1 -yl) - 1 -oxoisoindolin-2- yl)piperidine-2, 6-dione (referred to herein as “Compound A”)), which has the molecular formula of C45H49N5O4 and the following structure:Attorney Docket No.: 100C-401885-WOARVN0205W02Compound A is a Biopharmaceutics Classification System Class IV compound (low solubility / low permeability). Compound A can interconvert to its epimer, Compound B:Without wishing to be bound by theory, preclinical data indicates that the exposure of Compound B is limited compared to Compound A (<26%). Evidence indicates that Compound B does not degrade the ER; however, Compound B shows similar antagonism of ER-dependent transcription compared to Compound A.

[0020] In many cases, the compounds of this disclosure are capable of forming a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of the compounds described herein include the acid addition and base addition salts thereof. The term “pharmaceutically acceptable” as used herein indicates that the compound, or salt or composition thereof is compatible chemically and / or toxicologically with the other ingredients comprising a formulation and / or the subject being treated therewith.

[0021] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceuticallyAttorney Docket No.: 100C-401885-WOARVN0205W02 acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of NH3, or primary, secondary, tertiary amines.

[0022] Provided are also pharmaceutically acceptable acid addition salts of the compounds described herein. Suitable acid addition salts are formed from acids which form nontoxic salts. Non-limiting examples of suitable acid addition salts, i.e., salts containing pharmacologically acceptable anions, include, but are not limited to, the acetate, acid citrate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, bitartrate, borate, camsylate, citrate, cyclamate, edisylate, esylate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methanesulfonate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, p-toluenesulfonate, tosylate, trifluoroacetate and xinofoate salts.

[0023] Also provided are base addition salts of the compounds described herein. Suitable base addition salts are formed from bases that form non-toxic salts. Non-limiting examples of suitable base salts include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts.

[0024] The compounds described herein that are basic in nature can form a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds described herein are those that form nontoxic acid addition salts, e.g., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., l,l’-methylene-bis-(2-hydroxy-3-naphthoate)] salts. The compounds described hereinAttorney Docket No.: 100C-401885-WOARVN0205W02 that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.

[0025] The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of the compounds described herein that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

[0026] Hemisalts of acids and bases may also be formed, for example, hemisulphate, and hemicalcium salts.

[0027] For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of compounds described herein are known to one of skill in the art.

[0028] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0029] The term “administration” or “administering” refers to a method of giving a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian. The method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0030] An “amount” for use and for treating a subject refers to an amount that provides, in single or multiple doses, in combination with one or more other agents, a detectable response of any duration of time (transient, medium, or long term), a desired outcome in or an objective or subjective benefit to a subject of any measurable or detectable degree or for any duration of time (e.g., for hours, days, months, years, in remission or cured). Such amounts typically are effective to ameliorate a disease, or one, multiple or all adverse effects / symptoms, consequences, or complications of the disease, to a measurable extent, although reducing or inhibiting a progression or worsening of the disease, or providing stability (i.e., not worsening) state of the disease, is considered a satisfactory outcome.

[0031] The terms “effective amount” or “effective dosage” or “pharmaceutically effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entityAttorney Docket No.: 100C-401885-WOARVN0205W02 being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, and can include curing the disease. “Curing” means that the symptoms of active disease are eliminated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study. In some embodiments, a “therapeutically effective amount” of a compound as provided herein refers to an amount of the compound that is effective in the combination therapy of a method described herein.

[0032] In a treatment of cancer and / or tumor, the term “therapeutically effective amount” also means an amount of an agent in combination with one or more other agents, effective for producing a desired therapeutic effect upon administration to a subject, for example, to stem the growth, or result in the shrinkage, of a cancerous tumor. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount that has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis emergence, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, and / or (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer. Therapeutic or pharmacological effectiveness of the doses and administration regimens also may be characterized as the ability to induce, enhance, maintain, or prolong disease control and / or overall survival in patients with these specific tumors, which may be measured as prolongation of the time before disease progression.

[0033] As used herein, “ameliorate” refers to any reduction in the extent, severity, frequency, and / or likelihood of a symptom or clinical sign characteristic of a particular disease.

[0034] “Symptom” refers to any subjective evidence of disease or of a subject’s condition.

[0035] The term “excipient” or “pharmaceutical ly acceptable excipient” means a pharmaceutically- acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In some embodiments, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company:Attorney Docket No.: 100C-401885-WOARVN0205W022007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0036] The term “pharmaceutical composition” refers to a mixture of a compound or a pharmaceutical I y acceptable salt thereof as provided herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0037] The terms “treat,” “treating,” and “treatment,” in the context of treating a disease, disorder, or condition, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof.

[0038] The terms “treat” and “treating” a cancer or a cancer-associated disease, as used herein, mean to administer a combination therapy according to the present disclosure to a subject or patient having a cancer, or diagnosed with a cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth, reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The terms “treatment” and “therapy,” as used herein, unless otherwise indicated, refer to the act of treating as “treating” is defined immediately above. For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaying the progression the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and / or prolonging survival of patients the cancer. Positive therapeutic effects in cancer can be measured in a number of ways (see, for example, W. A. Weber, J. Nucl. Med. (2009) 50: 1S-10S).

[0039] The term “combination therapy” or variants of this term such as “Compound A or a pharmaceutically acceptable salt thereof in combination with a CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof,” “Compound A or a pharmaceutically acceptable salt thereof in combination with abemaciclib or a pharmaceutically acceptable salt thereof,” or “Compound A or aAttorney Docket No.: 100C-401885-WOARVN0205W02 pharmaceutically acceptable salt thereof in combination with ribociclib or a pharmaceutical I y acceptable salt thereof,” and the like, as used herein refers to a dosing regimen of two different therapeutically active agents (i.e., the components or combination partners of the combination), wherein the therapeutically active agents are administered together or separately in a manner prescribed by a medical care taker or according to a regulatory agency. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor such as abemaciclib or ribociclib, or a pharmaceutically acceptable salt thereof, are administered in the combination therapy of a method described herein.CDK4 / 6 Inhibitors

[0040] Cyclin-dependent kinases (CDKs) and related serine / threonine protein kinases are important cellular enzymes that perform essential f unctions in regulating eukaryotic cell division and proliferation. CDK catalytic units are activated by regulatory subunits known as cyclins. At least sixteen mammalian cyclins have been identified (Johnson DG, Walker CL. Cyclins and Cell Cycle Checkpoints. Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312). Cyclin B / CDK1, cyclin A / CDK2, cyclin E / CDK2, cyclin D / CDK4, cyclin D / CDK6, and likely other heterodynes are important regulators of cell cycle progression. Additional functions of cyclin / CDK heterodynes include regulation of transcription, DNA repair, differentiation, and apoptosis (Morgan DO, Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291).

[0041] CDK inhibitors have been demonstrated to be useful in treating cancer. Increased activity or temporally abnormal activation of cyclin-dependent kinases has been shown to result in the development of human tumors, and human tumor development is commonly associated with alterations in either the CDK proteins themselves or their regulators (Cordon-Cardo C. Mutations of cell cycle regulators: biological and clinical implications for human neoplasia. Am. J Pathol. (1995) 147:545-560; Karp JE, Broder S. Molecular foundations of cancer: new targets for intervention. Nat. Med. (1995) 1:309-320; Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and CDK inhibitors in human cancer. Adv. Cancer Res. (1996) 68:67-108).

[0042] CDK4 and CDK6 are important regulators of cell cycle progression at the Gl-S checkpoint, which are controlled by D-type cyclins and INK4 endogenous CDK inhibitors, such as p 16I K4' (CDKN2A). Dysregulation of the cyclin D-CDK4 / 6-INK4-retinoblastoma (Rb) pathway has been reported to be associated with development of endocrine therapy resistance.

[0043] Clinical trials for the CDK4 / 6 inhibitors palbociclib, ribociclib, and abemaciclib are ongoing for breast and other cancers, as single agents or in combination with other therapeutics. The use of CDK4 / 6 inhibitors in combination with endocrine therapy has demonstrated significant efficacy in the treatment of hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2) -negative advanced or metastatic breast cancers, and CDK4 / 6 inhibitors, including palbociclib, ribociclib, andAttorney Docket No.: 100C-401885-WOARVN0205W02 abemaciclib, have been approved in combination with endocrine therapy in a first-or second-line setting. Palbociclib, ribociclib, and abemaciclib have been approved for treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) -negative advanced or metastatic breast cancer in combination with aromatase inhibitors, such as letrozole, in a first line setting and with fulvestrant in second or later lines of therapy in certain patients. (O’Leary et al. Treating cancer with selective CDK4 / 6 inhibitors. Nature Reviews (2016) 13:417-30).

[0044] Cyclin-dependent kinases (CDKs) and related serine / threonine kinases are important cellular enzymes that perform essential functions in regulating cell division and proliferation. CDK inhibitors include Pan-CDK inhibitors that target a broad spectrum of CDKs or selective CDK inhibitors that target specific CDK(s).

[0045] Examples of CDK4 / 6 inhibitors include, but are not limited to, abemaciclib, ribociclib, and palbociclib. Additional examples of CDK4 / 6 inhibitors include lerociclib (also known as G1T38) and trilaciclib (also known as GTI128).

[0046] In some embodiments, the CDK4 / 6 inhibitor for use in a method described herein (e.g., for administration in combination with Compound A or a pharmaceutically acceptable salt thereof) is abemaciclib or ribociclib, or a pharmaceutically acceptable salt of each thereof.

[0047] Abemaciclib, A-(5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-l- isopropyl-2-methyl-lH-benzo[ti]imidazol-6-yl)pyrimidin-2-amine (e.g., as sold under the brand nameVerzenio® (and others)) is a selective inhibitor of CDK4 and CDK6, having the structure:

[0048] Abemaciclib and pharmaceutically acceptable salts thereof are disclosed in International Publication No. W02010 / 075074 and U.S. Patent No. 7,855,211. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0049] Ribociclib, 7-cyclopentyl-A,A-dimethyl-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)-7H- pyrrolo[2,3-ti]pyrimidine-6-carboxamide (e.g., as sold under the brand names Kisqali® and Kryxana®) is an inhibitor of cyclin D1 / CDK4 and CDK6, having the structure:Attorney Docket No.: 100C-401885-WOARVN0205W02

[0050] Ribociclib and pharmaceutically acceptable salts thereof are disclosed in International Publication Nos. W02007140222, WO2010 / 020675, W02012 / 064805 and WO2016 / 166703; and in U.S. Patent Nos. 8,324,225, 8,415,355, 8,685,980, 8,962,630, 9,193,732, 9,416,136, 9,868,739, and 10,799,506. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0051] In some embodiments, abemaciclib or a pharmaceutically acceptable salts thereof, is administered in a method described herein (e.g., administered in combination with Compound A or a pharmaceutically acceptable salt thereof).

[0052] In some embodiments, ribociclib or a pharmaceutically acceptable salts thereof, is administered in a method described herein (e.g., administered in combination with Compound A or a pharmaceutically acceptable salt thereof).Treatment Methods and Use

[0053] Provided are new therapeutic methods. In particular, the methods described herein can be useful for treating cancer (e.g., breast cancer such as ES'A7-mutant breast cancer) in a subject in need thereof, where the method comprises administering to the subject an effective amount (e.g., a daily dose) of Compound A or a pharmaceutically acceptable salt thereof in combination with an effective amount of a CDK4 / 6 inhibitor such as abemaciclib or ribociclib, or a pharmaceutically acceptable salt thereof.

[0054] The ESRI gene encodes the estrogen receptor alpha, a nuclear hormone receptor activated by estrogen. Estrogen receptor alpha is crucial in regulating gene expression related to cell growth and differentiation in breast tissue. While ESRI mutation are rare in primary, treatment-naive breast tumors, they are more common in metastatic, hormone receptor-positive breast cancers, especially after endocrine therapy. As further described in this disclosure, the method provided herein can be useful in treating ESRI -mutant breast cancer.

[0055] Accordingly, in some embodiments, provided is a method for treating ES'A7-mutant breast cancer in a subject in need thereof, comprising administering to the subject an effective amount of Compound A or a pharmaceutical I y acceptable salt thereof in combination with an effective amount of a CDK4 / 6 inhibitor such as abemaciclib or ribociclib, or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, provided is a method for treating ES'A7-mutant breast cancer in a subject in need thereof, comprising administering to the subject a daily dose of Compound A or a pharmaceutical I y acceptable salt thereof in combi nation with an effecti ve amount of abemaciclib or ribociclib, or a pharmaceutically acceptable salt of each thereof.

[0057] The ESRI mutation may be or may comprise at least one mutation selected from missense ESRI mutations between codons 310-547.Attorney Docket No.: 100C-401885-WOARVN0205W02

[0058] Additionally or alternatively, The ESRI mutation may be or may comprise at least one mutation selected from missense ESRI mutations between codons 310-547, K303R, V422del, and L549P.

[0059] In some embodiments, the ESRI mutation may be or may comprise at least one mutation selected from the group consisting of Y537X, D538X, E380X, L379X, V422X, S463X, L469X, and L536X, wherein “X” refers to any amino acid residue, other than the wild-type residue at that position. For example, “X” may refer to alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), praline (P), glycine (G), serine (S), threonine (T), cysteine (C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartate (D), or glutamate (E).

[0060] In some embodiments, the ESRI mutation may be or may comprise a mutation selected from the group consisting of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, wherein “X” refers to any amino acid residue, other than the wild-type residue at that position. For example, “X” may refer to alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), praline (P), glycine (G), serine (S), threonine (T), cysteine (C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartate (D), or glutamate (E).

[0061] In some embodiments, the ESRI mutation may be or may comprise Y537X.

[0062] In some embodiments, the ESRI mutation may be or may comprise D538X.

[0063] In some embodiments, the ESRI mutation may be or may comprise E380X.

[0064] In some embodiments, the ESRI mutation may be or may comprise L379X.

[0065] In some embodiments, the ESRI mutation may be or may comprise V422X.

[0066] In some embodiments, the ESRI mutation may be or may comprise S463X.

[0067] In some embodiments, the ESRI mutation may be or may comprise L469X.

[0068] In some embodiments, the ESRI mutation may be or may comprise L536X.

[0069] In some embodiments, the ESRI mutation may be or may comprise at least one mutation selected from the group consisting of Y537S, Y537N, Y537C / S / N, D538G, E380Q, L379I, V392I, V422del, V534E, S463P, P535H, R555S, L536P, L536R, and L536_D538>P.

[0070] In some embodiments, the ESRI mutation may be or may comprise a mutation selected from the group consisting of Y537S, Y537N, Y537C / S / N, D538G, E380Q, L379I, V392I, V422del, V534E, S463P, P535H, R555S, L536P, L536R, and L536_D538>P.

[0071] In some embodiments, the ESRI mutation may be or may comprise Y537S.

[0072] In some embodiments, the ESRI mutation may be or may comprise Y537N.Attorney Docket No.: 100C-401885-WOARVN0205W02

[0073] In some embodiments, the ESRI mutation may be or may comprise Y537C / S / N.

[0074] In some embodiments, the ESRI mutation may be or may comprise D538G.

[0075] In some embodiments, the ESRI mutation may be or may comprise E380Q.

[0076] In some embodiments, the ESRI mutation may be or may comprise L379I.

[0077] In some embodiments, the ESRI mutation may be or may comprise V392I.

[0078] In some embodiments, the ESRI mutation may be or may comprise V422del.

[0079] In some embodiments, the ESRI mutation may be or may comprise V534E.

[0080] In some embodiments, the ESRI mutation may be or may comprise S463P.

[0081] In some embodiments, the ESRI mutation may be or may comprise P535H.

[0082] In some embodiments, the ESRI mutation may be or may comprise R555S.

[0083] In some embodiments, the ESRI mutation may be or may comprise L536P.

[0084] In some embodiments, the ESRI mutation may be or may comprise L536R.

[0085] In some embodiments, the ESRI mutation may be or may comprise L536_D538>P.

[0086] Those skilled in the art will be able to recognize and diagnose cancers comprising a gene mutation, such as a ESRI -mutant breast cancer in a patient or subject.

[0087] In some embodiments, the breast cancer (e.g., the ES7 / -mutant breast cancer) is locally advanced or metastatic.

[0088] In some embodiments, the breast cancer (e.g., the ES7 / -mutant breast cancer) is metastatic breast cancer (e.g., ES7 / -mutant metastatic breast cancer).

[0089] Metastatic breast cancer, or metastases, refers to breast cancer that has spread beyond the breast and nearby lymph nodes to other parts of the body, e.g., bones, liver, lungs, brain.

[0090] In some embodiments, the breast cancer (e.g., the ESRI -mutant breast cancer) is locally advanced breast cancer (e.g., ES7 / -mutant locally advanced breast cancer).

[0091] Locally advanced breast cancer (LABC) is defined by the U.S. National Comprehensive Cancer Network as a subset of breast cancer characterized by the most advanced breast tumors in the absence of distant metastasis, wherein the tumors are more than 5 cm in size with regional lymphadenopathy; tumors of any size with direct extension to the chest wall or skin, or both (including ulcer or satellite nodules), regardless of regional lymphadenopathy; presence of regional lymphadenopathy (clinically fixed or matted axillary lymph nodes, or any of infraclavicular, supraclavicular, or internal mammary lymphadenopathy) regardless of tumor stage. (Garg et al. CurrAttorney Docket No.: 100C-401885-WOARVN0205W02Oncol. 2015 Oct; 22(5): e409-e410; National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Fort Washington, PA: NCCN; 2015. Ver. 2.2015.)

[0092] Those skilled in the art will be able to recognize and diagnose locally advanced and metastatic cancer in a patient or subject.

[0093] In embodiments, the breast cancer (e.g., the ES'A7-mutant breast cancer) is hormone receptor positive (HR+) breast cancer (e.g., ES'A7-miitant HR+ breast cancer).

[0094] HR+ breast cancer cells have either estrogen (ER) or progesterone (PR) receptors or both. Accordingly, the HR+ breast cancer may be progesterone receptor positive (PR+) and / or estrogen receptor positive (ER+) breast cancer.

[0095] In embodiments, the breast cancer (e.g., the ESRI -mutant breast cancer) is PR+ breast cancer (e.g., S'A7-miitant PR+ breast cancer).

[0096] In some embodiments, the breast cancer (e.g., the S'A7-miitant breast cancer) is ER+ breast cancer (e.g., S'A7-miitant ER+ breast cancer).

[0097] ER+, estrogen receptor positive, as used herein, refers to breast cancer cells that have a receptor protein that binds the hormone estrogen. Cancer cells that are ER+ may need estrogen to grow, and may stop growing or die when treated with substances that block the binding and actions of estrogen.

[0098] In some embodiments, the breast cancer (e.g., the ES'A7-mutant breast cancer) is human epidermal growth factor receptor 2 negative (HER2-) breast cancer (e.g., ESRI -mutant HER2- breast cancer).

[0099] HER2-, human epidermal growth factor receptor 2 negative, as used herein, refers to breast cancer cells that does not have a large amount of a protein called HER2 on their surface. In normal cells, HER2 helps to control cell growth. Cancer cells that are HER2- may grow more slowly and are less likely to recur or spread to other parts of the body than cancer cells that have a large amount of HER2 on their surface.

[0100] In some embodiments, the breast cancer (e.g., the ESRI -mutant breast cancer) is human epidermal growth factor receptor 2 positive (HER2+) breast cancer (e.g., ES'A7-mutant HER2+ breast cancer).

[0101] In some embodiments, the breast cancer (e.g., the ESRI -mutant breast cancer) is ER+ HER2- breast cancer (e.g., ES'A7-mutant ER+ HER2- breast cancer).

[0102] In some embodiments, the breast cancer (e.g., the ESRI -mutant breast cancer) is ER+ HER2+ breast cancer (e.g., ES'A7-mutant ER+ HER2+ breast cancer).Attorney Docket No.: 100C-401885-WOARVN0205W02

[0103] In some embodiments, the breast cancer (e.g., the ESRI -mutant breast cancer) is locally advanced or metastatic ER+ breast cancer (e.g., S'A7-mutant locally advanced or metastatic ER+ breast cancer).

[0104] In some embodiments, the breast cancer (e.g., the ESRI -mutant breast cancer) is locally advanced ER+ breast cancer (e.g., S'A7-mutant locally advanced ER+ breast cancer).

[0105] In some embodiments, the breast cancer (e.g., the ESRI -mutant breast cancer) is metastatic ER+ breast cancer (e.g., S'A7-miitant metastatic ER+ breast cancer).

[0106] In some embodiments, the breast cancer (e.g., the ESRI -mutant breast cancer) is locally advanced or metastatic ER+ HER2- breast cancer (e.g., S'A7-mutant locally advanced or metastatic ER+ HER2-breast cancer).

[0107] In some embodiments, the breast cancer (e.g., the ESRI -mutant breast cancer) is locally advanced ER+ HER2- breast cancer (e.g., S'A7-miitant locally advanced ER+ HER2-breast cancer).

[0108] In some embodiments, the breast cancer (e.g., the ESRI -mutant breast cancer) is metastatic ER+ HER2- breast cancer (e.g., S'A7-miitant metastatic ER+ HER2-breast cancer).

[0109] In some embodiments, the breast cancer (e.g., the ESRI -mutant breast cancer) is locally advanced or metastatic ER+ HER2+ breast cancer (e.g., S'A7-mutant locally advanced or metastatic ER+ HER2+ breast cancer).

[0110] In some embodiments, the breast cancer (e.g., the ESRI -mutant breast cancer) is locally advanced ER+ HER2+ breast cancer (e.g., S'A7-miitant locally advanced ER+ HER2+ breast cancer).

[0111] In some embodiments, the breast cancer (e.g., the ESRI -mutant breast cancer) is metastatic ER+ HER2+ breast cancer (e.g., S'A7-miitant metastatic ER+ HER2+ breast cancer).

[0112] In some embodiments, both locally advanced breast cancer (e.g., locally advanced ER+ breast cancer, locally advanced HER2- breast cancer, locally advanced ER+ HER2+ breast cancer, or locally advanced ER+ HER2- breast cancer) and metastatic breast cancer (e.g., metastatic ER+ breast cancer, metastatic HER2- breast cancer, metastatic ER+ HER2+ breast cancer, or metastatic ER+ HER2- breast cancer) are present in the subject.

[0113] In some embodiments, the breast cancer (e.g., the ESRI -mutant breast cancer) is CDK4 / 6 inhibitor resistant (e.g., breast cancer that no longer responds to a treatment with a CDK4 / 6 inhibitor) breast cancer (e.g., ES'A7-miitant CDK4 / 6 inhibitor resistant breast cancer).

[0114] In accordance with any embodiments described herein, the subject may have received a CDK4 / 6 inhibitor-based therapy prior to administration of the compounds of a method described herein (e.g., prior to administration of Compound A, abemaciclib, or ribociclib, or a pharmaceutically acceptable salt thereof). For example, the subject may have previously received one or two lines ofAttorney Docket No.: 100C-401885-WOARVN0205W02 anti-cancer therapy. In some embodiments, the subject has previously received one or two lines of anti-cancer therapy (e.g., one or two lines of anti-cancer therapy for the treatment of advanced and / or metastatic cancer), wherein one line of the one or two lines of anti-cancer therapy is a CDK4 / 6 inhibitor-based therapy. Exemplary CDK4 / 6 inhibitors for use in the previous CDK4 / 6 inhibitorbased therapy include ribociclib, palbociclib, and abemaciclib.

[0115] In some embodiments, the subject did not require a dose reduction due to an adverse event during the previous CDK4 / 6 inhibitor-based therapy.

[0116] In some embodiments, the subject has received fulvestrant prior to administration of the compounds of a method described herein (e.g., prior to administration of Compound A, abemaciclib, or ribociclib, or a pharmaceutically acceptable salt thereof).

[0117] In some embodiments, the subject has received an aromatase inhibitor-based therapy prior to administration of the compounds of a method described herein (e.g., prior to administration of Compound A, abemaciclib, or ribociclib, or a pharmaceutically acceptable salt thereof).

[0118] In some embodiments, the subject has received chemotherapy prior to administration of the compounds of a method described herein (e.g., prior to administration of Compound A, abemaciclib, or ribociclib, or a pharmaceutically acceptable salt thereof).

[0119] In some embodiments, the subject has disease progressed on or is resistant to a standard therapy for treating cancer (e.g., a standard therapy for treating breast cancer).

[0120] In some embodiments, the subject has disease progressed on or is resistant to a treatment with a CDK4 / 6 inhibitor (e.g., the subject no longer responds to a treatment with a CDK4 / 6 inhibitor).

[0121] Also disclosed herein are methods of treating solid tumors in a subject in need thereof. In some embodiments, disclosed herein is a method of treating solid tumors in a subject in need thereof, where the method comprises administering to the subject an effective amount (e.g., a daily dose) of Compound A or a pharmaceutical ly acceptable salt thereof in combination with an effective amount of a CDK4 / 6 inhibitor such as abemaciclib or ribociclib, or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, disclosed herein is a method of treating solid tumors in a subject in need thereof, where the method comprises administering to the subject a daily dose of Compound A or a pharmaceutically acceptable salt thereof in combination with an effective amount of abemaciclib or ribociclib, or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, the solid tumor is a breast cancer as described herein. In some embodiments, the solid tumor is ES'A7-mutant breast cancer.

[0124] In some embodiments, the solid tumor is locally advanced or metastatic breast cancer (e.g., ESRI -mutant locally advanced or metastatic breast cancer).Attorney Docket No.: 100C-401885-WOARVN0205W02

[0125] In some embodiments, the solid tumor is locally advanced breast cancer (e.g., ESRI -mutant locally advanced breast cancer).

[0126] In some embodiments, the solid tumor is metastatic breast cancer (e.g., ESA mutant metastatic breast cancer).

[0127] I In some embodiments, the solid tumor is hormone receptor positive (HR+) breast cancer (e.g., ESRI -mutant HR+ breast cancer).

[0128] In some embodiments, the solid tumor is PR+ breast cancer (e.g., ESA mutant PR+ breast cancer).

[0129] In some embodiments, the solid tumor is ER+ breast cancer (e.g., ESA mutant ER+ breast cancer).

[0130] In some embodiments, the solid tumor is human epidermal growth factor receptor 2 negative (HER2-) breast cancer (e.g., ESA mutant HER2- breast cancer).

[0131] In some embodiments, the solid tumor is human epidermal growth factor receptor 2 positive (HER2+) breast cancer (e.g., ESA mutant HER2+ breast cancer).

[0132] In some embodiments, the solid tumor is ER+ HER2- breast cancer (e.g., ESA mutant ER+ HER2- breast cancer).

[0133] In some embodiments, the solid tumor is ER+ HER2+ breast cancer (e.g., ESA mutant ER+ HER2+ breast cancer).

[0134] In some embodiments, the solid tumor is locally advanced or metastatic ER+ breast cancer (e.g., ESRI -mutant locally advanced or metastatic ER+ breast cancer).

[0135] In some embodiments, the solid tumor is locally advanced ER+ breast cancer (e.g., ESR1- mutant locally advanced ER+ breast cancer).

[0136] In some embodiments, the solid tumor is metastatic ER+ breast cancer (e.g., ESA mutant metastatic ER+ breast cancer).

[0137] In some embodiments, the solid tumor is locally advanced or metastatic ER+ HER2- breast cancer (e.g., ESRI -mutant locally advanced or metastatic ER+ HER2-breast cancer).

[0138] In some embodiments, the solid tumor is locally advanced ER+ HER2- breast cancer (e.g., ESA mutant locally advanced ER+ HER2-breast cancer).

[0139] In some embodiments, the solid tumor is metastatic ER+ HER2- breast cancer (e.g., ESR1- mutant metastatic ER+ HER2-breast cancer).

[0140] In some embodiments, the solid tumor is locally advanced or metastatic ER+ HER2+ breast cancer (e.g., ESRI -mutant locally advanced or metastatic ER+ HER2+ breast cancer).Attorney Docket No.: 100C-401885-WOARVN0205W02

[0141] In some embodiments, the solid tumor is locally advanced ER+ HER2+ breast cancer (e.g., ES'A7-mutant locally advanced ER+ HER2+ breast cancer).

[0142] In some embodiments, the solid tumor is metastatic ER+ HER2+ breast cancer (e.g., ESR1- mutant metastatic ER+ HER2+ breast cancer).

[0143] In some embodiments, the solid tumor comprises both locally advanced breast cancer (e.g., locally advanced ER+ breast cancer, locally advanced HER2- breast cancer, locally advanced ER+ HER2+ breast cancer, or locally advanced ER+ HER2- breast cancer) and metastatic breast cancer (e.g., metastatic ER+ breast cancer, metastatic HER2- breast cancer, metastatic ER+ HER2+ breast cancer, or metastatic ER+ HER2- breast cancer) are present in the subject.

[0144] In some embodiments, the solid tumor is a CDK4 / 6 inhibitor resistant breast cancer (e.g., ES'A7-mutant CDK4 / 6 inhibitor resistant breast cancer).

[0145] The methods described herein may lead to a reduction in tumor size. Additionally or alternatively, the cancer may be metastatic cancer and the method described herein may lead to inhibition of metastatic cancer cell invasion.Pharmaceutical Compositions

[0146] The compounds for use in a method described herein (e.g., Compound A, abemaciclib, ribociclib, or a pharmaceutically acceptable salt thereof) may be present in a pharmaceutical composition, which includes a pharmaceutically acceptable excipient. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0147] The pharmaceutical compositions can be prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0148] The compounds of a method described herein (e.g., Compound A, abemaciclib, ribociclib, or a pharmaceutically acceptable salt thereof) may be formulated prior to administration. The formulation preferably will be adapted to the particular mode of administration. These compounds may be formulated with pharmaceutically acceptable excipients as known in the art and administered in a wide variety of dosage forms as known in the art. Dosage unit forms or pharmaceutical compositions suitable for oral administration include, but are not limited to tablets, capsules, such as gelatin capsules, pills, powders, granules, aqueous, and nonaqueous oral solutions and suspensions, packaged in containers adapted for subdivision into individual doses.Attorney Docket No.: 100C-401885-WOARVN0205W02Administration and Treatment Regimens

[0149] The compounds of a method described herein (e.g., Compound A, abemaciclib, ribociclib, or a pharmaceutically acceptable salt thereof) may be administered to a subject in need thereof according to the invention by any appropriate route, including oral, parenteral (subcutaneous, intramuscular, intravenous (bolus or infusion), depot, intraperitoneal), intrathecal, intranasal, intravaginal, sublingual, buccal, intraocular, or rectal. In some embodiments, the compounds disclosed herein may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.

[0150] In accordance with any embodiments described herein, Compound A or a pharmaceutically acceptable salt thereof may be administered in combination with a CDK4 / 6 inhibitor such as abemaciclib or ribociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof and the CDK4 / 6 inhibitor such as abemaciclib or ribociclib, or a pharmaceutically acceptable salt thereof, are administered intermittently, concurrently, or sequentially, according to the same or different route of administration and according to the same or different dosage schedules.

[0151] In some embodiments, the compounds of a method described herein (e.g., Compound A, abemaciclib, ribociclib, or a pharmaceutically acceptable salt thereof) are administered to a subject in a fasted state. For example, in some embodiments, the subject has not eaten for, e.g., at least 4 hours before a time point of interest, such as the time of administering the compounds of a method described herein. In some embodiment, a subject in the fasted state has not eaten for at least any of 6, 8, 10 or 12 hours prior to administration of the compounds of a method described herein.

[0152] In some embodiments, the compounds of a method described herein (e.g., Compound A, abemaciclib, ribociclib, or a pharmaceutically acceptable salt thereof) are administered to a subject in a fed state. For example, in some embodiments, the subject has eaten, e.g., less than 4 hours before a time point of interest, such as the time of administering the compounds of a method described herein. In some embodiments, a subject in the fed state has eaten within any of 4, 3, 2, 1, or 0.5 hours prior to administration of the compounds of a method described herein.Doses and Dosing Regimens

[0153] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered (e.g., administered orally) to a subject at an effective amount. In some embodiments, the effective amount is a daily dose of about 100 mg or about 200 mg of Compound A. In some embodiments, the effective amount is a daily dose of about 100 mg of Compound A. In someAttorney Docket No.: 100C-401885-WOARVN0205W02 embodiments, the effective amount is a daily dose of about 200 mg of Compound A. Dosage amounts, provided herein, refer to the dose of the free base form of Compound A, or are calculated as the free base equivalent of an administered Compound A salt form. For example, a dosage or amount of Compound A, such as 200 mg or 100 mg, refers to the free base equivalent.

[0154] In embodiments, the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered once per day (QD).

[0155] In some embodiments, Compound A is administered as a free base.

[0156] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered in combination with abemaciclib or a pharmaceutically acceptable salt thereof. In some embodiments, abemaciclib or a pharmaceutically acceptable salt thereof is administered (e.g., administered orally) at an effective amount.

[0157] In some embodiments, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered (e.g., administered orally) at a daily dosage of about 400 mg (e.g., about 200 mg twice daily), about 300 mg (e.g., about 150 mg twice daily), about 200 mg (e.g., about 100 mg twice daily), or about 100 mg (e.g., about 50 mg twice daily). Dosage amounts, provided herein, refer to the dose of the free base form of abemaciclib, or are calculated as the free base equivalent of an administered abemaciclib salt form. For example, a dosage or amount of abemaciclib, such as 200 mg, 150 mg, 100 mg, or 50 mg, refers to the free base equivalent.

[0158] In some embodiments, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered (e.g., administered orally) at a daily dosage of about 300 mg (e.g., about 150 mg twice daily) or about 200 mg (e.g., about 100 mg twice daily).

[0159] In some embodiments, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered (e.g., administered orally) at a daily dosage of 300 mg (e.g., about 150 mg twice daily).

[0160] In some embodiments, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered (e.g., administered orally) at a dose of about 200 mg (e.g., about 100 mg twice daily).

[0161] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered (e.g., administered orally) at a dose of about 200 mg once daily and abemaciclib, or a pharmaceutically acceptable salt thereof, is administered (e.g., administered orally) at a dose of about 150 mg twice daily.

[0162] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered (e.g., administered orally) at a dose of about 100 mg once daily and abemaciclib, or a pharmaceutically acceptable salt thereof, is administered (e.g., administered orally) at a dose of about 150 mg twice daily.Attorney Docket No.: 100C-401885-WOARVN0205W02

[0163] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered (e.g., administered orally) at a dose of about 200 mg once daily and abemaciclib, or a pharmaceutically acceptable salt thereof, is administered (e.g., administered orally) at a dose of about 100 mg twice daily.

[0164] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered (e.g., administered orally) at a dose of about 100 mg once daily and abemaciclib, or a pharmaceutically acceptable salt thereof, is administered (e.g., administered orally) at a dose of about 100 mg twice daily.

[0165] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered in combination with ribociclib or a pharmaceutical I y acceptable salt thereof.

[0166] In some embodiments, ribociclib, or a pharmaceutically acceptable salt thereof, is administered at a daily dosage of about 600 mg once daily, about 400 mg once daily, about 200 mg once daily, or about 50 mg once daily. Dosage amounts, provided herein, refer to the dose of the free base form of ribociclib, or are calculated as the free base equivalent of an administered ribociclib salt form. For example, a dosage or amount of ribociclib, such as 600 mg, 400 mg, 200 mg, or 50 mg refers to the free base equivalent.

[0167] In some embodiments, ribociclib, or a pharmaceutically acceptable salt thereof, is administered at a daily dosage of about 600 mg or about 400 mg once daily.

[0168] In some embodiments, ribociclib, or a pharmaceutically acceptable salt thereof, is administered at a daily dosage of about 600 mg once daily.

[0169] In some embodiments, ribociclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 400 mg once daily.

[0170] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered (e.g., administered orally) at a dose of about 200 mg once daily and ribociclib, or a pharmaceutically acceptable salt thereof, is administered (e.g., administered orally) at a dose of about 600 mg once daily.

[0171] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered (e.g., administered orally) at a dose of about 100 mg once daily and ribociclib, or a pharmaceutically acceptable salt thereof, is administered (e.g., administered orally) at a dose of about 600 mg once daily.

[0172] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered (e.g., administered orally) at a dose of about 200 mg once daily and ribociclib, or a pharmaceutically acceptable salt thereof, is administered (e.g., administered orally) at a dose of about 400 mg once daily.Attorney Docket No.: 100C-401885-WOARVN0205W02

[0173] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered (e.g., administered orally) at a dose of about 100 mg once daily and ribociclib, or a pharmaceutically acceptable salt thereof, is administered (e.g., administered orally) at a dose of about 400 mg once daily.

[0174] Repetition of the administration or dosing regimens may be conducted as necessary to achieve the desired reduction or diminution of cancer cells. A “continuous dosing schedule,” as used herein, is an administration or dosing regimen without dose interruptions, e.g., without days off treatment. Repetition of 28-day treatment cycles without dose interruptions between the treatment cycles is an example of a continuous dosing schedule. In embodiments, the compounds of a method described herein (e.g., the compounds of the combination therapy as described herein) can be administered in a continuous dosing schedule. In embodiments, the compounds a method described herein (e.g., the compounds of the combination therapy as described herein) can be administered concurrently in a continuous dosing schedule.

[0175] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered once daily to comprise a complete cycle of 28-days. Repetition of 28-day treatment cycles may be continued during treatment in accordance with the methods and uses of the present disclosure. Repetition of the 28-day cycles may be continued during treatment with the combination of the present invention.

[0176] In some embodiments, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered once daily to comprise a complete cycle of 28-days. Repetition of 28-day treatment cycles may be conti nued during treatment in accordance with the methods and uses of the present disclosure. Repetition of the 28-day cycles may be continued during treatment with the combination of the present invention.

[0177] In some embodiments, ribociclib, or a pharmaceutically acceptable salt thereof, is administered once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28-days. Repetition of 28-day treatment cycles may be continued during treatment in accordance with the methods and uses of the present disclosure. Repetition of the 28-day cycles may be continued during treatment with the combination of the present invention.Kits

[0178] Also disclosed herein are kits comprising the therapeutic agents of a method described herein (e.g., the compounds of the combination therapy as described herein) and written instructions for administration of the therapeutic agents. In embodiments, the written instructions elaborate and qualify the modes of administration of the therapeutic agents, for example, for simultaneous or sequential administration of the therapeutic agents of the present disclosure. In embodiments, the written instructions elaborate and qualify the modes of administration of the therapeutic agents, forAttorney Docket No.: 100C-401885-WOARVN0205W02 example, by specifying the days of administration for each of the therapeutic agents during a 28-day treatment cycle.Examples

[0179] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to f unction well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

[0180] Abbreviations used herein include:• AUCtau = area under the plasma concentration-time curve over the dosing interval, where tau= 24 hours for once daily dosing and 12 hours for twice daily dosing;• CI = confidence interval;• CR= complete response• CBR = clinical benefit rate;• Cm x = maximum plasma concentration;• DLT = dose-limiting toxicities• ER = estrogen receptor;• HER2 = human epidermal growth factor receptor 2;• mBC = metastatic breast cancer;• ORR = overall response rate;• PD = progressive disease;• PO = oral administration• PR = partial response• QD = once daily;• SD = stable disease; and• TRAE = treatment-related adverse event.Example 1. In Vivo Efficacy Evaluation of Compound A in Combination with Abemaciclib or Ribociclib in XenoSTART Patient-Derived Xenograft (XPDX) Models

[0181] An in vivo study was conducted to evaluate the efficacy of Compound A in combination with abemaciclib or ribociclib in XenoSTART Padent-Derived Xenograft (XPDX) models representing human breast cancer, re-derived to be palbociclib resistant ( / PBR), in immune-deficient mice. TheAttorney Docket No.: 100C-401885-WGARVN0205W02 mice models were generated using ST941-PBR (palbociclib resistant; estrogen receptor gene [ESRI] Y537S) tumor fragments.

[0182] Materials:

[0183] Species. Female athymic nude (Crl:NU(NCr)-Foxnlnu) or CB-17 SCID (CB17 / Icr- Prkdcscld / IcrIcoCrl) mice, between 6-12 weeks of age, weighing an approximate minimum of 20 grams on Day 0.

[0184] Animal Handling. Mice were fed water ad libitum (reverse osmosis, 2 ppm Ch) and an irradiated standard rodent diet consisting of 19% protein, 9% fat, and 4% fiber.

[0185] Tumor Models. XPDX models were established from viable human tumor tissue or fluid that had been serially passaged in animals a limited number of times to maintain tumor heterogeneity. In subcutaneous models, athymic nude or CB-17 SCID mice were implanted unilaterally on the flank with tumor fragments harvested from host animals each implanted from a specific passage lot.

[0186] Methods. When mean tumor volume reached 250 mm3, mice were assigned to treatment and control groups (n=8 per group). Mice were dosed with vehicle, vepdegestrant 30 mg / kg, abemaciclib 50 mg / kg, ribociclib 150 mg / kg, vepdegestrant 30 mg / kg plus abemaciclib 50 mg / kg, or vepdegestrant 30 mg / kg plus ribociclib 150 mg / kg. Vepdegestrant, abemaciclib, and ribociclib were administered orally once daily. All mice received continuous treatment for 35 days; all arms were then taken off treatment, and tumor growth was monitored up to day 41. Mice were observed once daily, weight and tumor dimension data was collected twice weekly.

[0187] Efficacy Calculations. A percent tumor growth inhibition (%TGI) value was calculated for each treatment group (T) versus control (C) using initial (i) and final (f) tumor measurements using the following formula: %TGI = 1 - (Tf- T0 / (Cf- Ci).

[0188] Results. No significant loss in mouse bodyweight was observed for any single agents or combination. In combination with abemaciclib or ribociclib, vepdegestrant displayed greater antitumor activity (abemaciclib combination: 106% TGI, ribociclib combination: 105% TGI) than that observed with vepdegestrant alone (92% TGI) in the ST941-PBR model (FIG. 1).Attorney Docket No.: 100C-401885-WOARVN0205W02Example 2. Vepdegestrant in Combination with Abemaciclib in Estrogen Receptor- Positive / Human Epidermal Growth Factor Receptor 2-Negative Advanced or Metastatic Breast CancerExample 2A

[0189] A phase lb clinical trial was conducted to evaluate the safety, clinical activity, and pharmacokinetics (PK) of Compound A in combination with abemaciclib in previously treated patients with ER-positive (ER+) / human epidermal growth factor 2-negative (HER2-) advanced breast cancer.

[0190] Key eligibility criteria were as follows:• Histologically or cytologically confirmed ER+ / HER2- advanced or metastatic breast cancer not amenable to surgical resection with curative intent• >1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST vl.l)• 1 or 2 prior therapies for advanced / metastatic disease; 1 line of prior CDK4 / 6 inhibitor-based regimen in any setting was required, and patients who needed a dose reduction due to an adverse event (AE) with previous CDK4 / 6 inhibitor therapy were excluded• Eastern Cooperative Oncology Group performance status <1

[0191] Methods. Following a 7-day PK lead-in with abemaciclib administered alone in a subset of patients, all patients received vepdegestrant 200 mg orally once daily and abemaciclib 150 mg orally twice daily (both continuously).

[0192] Endpoints. The primary endpoint of the study was DLTs in the first cycle; secondary endpoints included safety, PK (plasma concentrations of abemaciclib and active metabolites, N- desethylabemaciclib [M2], hydroxy-N-desethylabemaciclib [M18], and hydroxyabemaciclib [M20]), and antitumor activity (CBR and ORR).

[0193] Baseline Characteristics. 16 patients received vepdegestrant in combination with abemaciclib in this study, the corresponding demographics and baseline characteristics are summarized in Table 1. Of the 16 patients, 100% received prior CDK4 / 6 inhibitors, 88% received prior aromatase inhibitors, 31% received prior fulvestrant, and 69% received prior chemotherapy (31% in the metastatic setting).Attorney Docket No.: 100C-401885-WOARVN0205W02Table 1: Demographics and baseline characteristicsAttorney Docket No.: 100C-401885-WO ARVN0205W02

[0194] Safety. As shown in Table 2, there were no dose-limiting toxicides (DLTs) or grade 4 / 5 TEAEs. Grade 3 TEAEs led to dose reductions of vepdegestrant were observed in 2 (13%) patients, and TEAEs led to dose reductions of abemaciclib were observed in 7 (44%) patients. Additionally, as shown in Table 3, treatment-related adverse events reported in >10% of patients were mostly grade 1 / 2. Specifically, neutropenia of any grade was observed in 6 patients (38%) and grade 3 treatment- related neutropenia occurred in 5 patients (31%), which was manageable with dose modifications.Table 2: Summary of treatment-emergent adverse event (TEAE)Table 3: TEAEs attributed to either vepdegestrant or abemaciclib in >10% of patientsAttorney Docket No.: 100C-401885-WOARVN0205W02

[0195] Efficacy. The clinical benefit rate (CBR) and objective response rate (ORR) of this study are provided in Table 4. CBR among all patients was 62.5% (95% CI: 38.6-81.5), and ORR among patients with measurable disease at baseline was 26.7% (95% CI: 10.9-52.0). It was found that CBR was the same in patients with and without mutations in the estrogen receptor 1 gene (ESRI; CBR: 62.5%; 95% CI: 30.6-86.3), and ORR was 37.5% (95% CI: 13.7-69.4) and 14.3% (95% CI: 2.6- 51.3), respectively. Further, four patients had confirmed partial response and six patients had stable disease for >24 weeks per RECIST vl.l (FIG. 2). As shown in FIG. 3, the median treatment duration was ~6.6 months. 12 patients received vepdegestrant and abemaciclib for >4 cycles and 11 patients received vepdegestrant and abemaciclib for >5 cycles, 5 were ongoing at the time of data cutoff.Table 4: Summary of CBR and ORRAttorney Docket No.: 100C-401885-WOARVN0205W02

[0196] Pharmacokinetics. Area under the concentration-time curve from time 0 to time tau (AUCtau) and maximum observed concentration (Cmax) of abemaciclib increased slightly, 13% and 16%, respectively, when dosed with vepdegestrant compared with abemaciclib alone (Table 5). These preliminary PK data showed no significant drug interaction.Table 5: Plasma PK parametersExample 2B

[0197] A phase 2 clinical trial was conducted using a method similar to that described in Example 2A.

[0198] Key eligibility criteria were as follows:• ER+ / HER2- advanced or metastatic breast cancer not amenable for surgery;• >1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST vl.l)• 1 or 2 prior therapies for advanced / metastatic disease:• % 1 line of prior chemotherapy (no antibody-drug conjugates permitted);• % 2 lines of prior endocrine-based therapies ;Attorney Docket No.: 100C-401885-WOARVN0205W02• No prior elacestrant or experimental endocrine therapy (eg, SERD, CERAN, PROTAC, SERCA) permitted;• Pre- / peri / post-menopausal women / men (LHRH (luteinizing hormone-releasing hormone) agonist for pre- / peri menopausal women and men)

[0199] Baseline Characteristics. 21 patients received vepdegestrant in combination with abemaciclib in this study. Of the 21 patients, 12 patients (57.1%) exhibited an ESRI mutation, while 9 patients (42.9%) did not. Additionally, of the 21 patients, 100% received prior aromatase inhibitors, 42.9% received prior fulvestrant, 100% received prior CDK4 / 6 inhibitors, 4.8% received prior PI3K inhibitors, 14.3% received prior mTOR inhibitors, and 85.7% received prior chemotherapy (14.3% in the metastatic setting).

[0200] Efficacy. The clinical benefit rate (CBR) and objective response rate (ORR) of this phase 2 study were analyzed. The CBR was 41%, and the ORR was 23.8%.Overall results based on Example 2A and Example 2B

[0201] A total of 37 patients received vepdegestrant in combination with abemaciclib in the study. Of these, 20 patients (54.1%) exhibited an ESRI mutation, while 17 patients (45.9%) did not.

[0202] The overall CBR and ORR were 54.8% and 27.8%, respectively.

[0203] The overall CBR differentiated between subgroups. Specifically, the CBR was 62.5% in patients with ESRI mutations and 46.7% in patients without mutations.

[0204] The overall ORR was more differentiated between subgroups. Specifically, the ORR was 45% in patients with ESRI mutations and 6.3% in patients without mutations.

[0205] Safety analysis was consistent with findings from Example 2A.

[0206] Pharmacokinetics analysis was also consistent with Example 2A. No significant drug interaction was observed between vepdegestrant and abemaciclib. The relative potency-adjusted unbound AUCtaufor abemaciclib and its metabolites increased by 22%, compared to a 15% increase observed in Example 2A.* * *

[0207] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0208] The disclosure illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising”, “including,” “containing”, etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intendon in the use of such terms and expressions ofAttorney Docket No.: 100C-401885-WOARVN0205W02 excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure.

[0209] Thus, it should be understood that although the present disclosure has been specifically disclosed by certain embodiments and optional features, modification, improvement and variation of the disclosure embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications, improvements and variations are considered to be within the scope of this disclosure. The materials, methods, and examples provided here are representative of certain embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure.

[0210] The disclosure has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the disclosure. This includes the generic description of the disclosure with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0211] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0212] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control.

[0213] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Claims

Attorney Docket No.: 100C-401885-WOARVN0205W02CLAIMS:

1. A method for treating ESR 7-mutant breast cancer comprising administering to a subject in need thereof a daily dose of Compound A:(Compound A), or a pharmaceutically acceptable salt thereof, in combination with abemaciclib or ribociclib, or a pharmaceutically acceptable salt of each thereof.

2. The method of claim 1, wherein the abemaciclib or ribociclib, or a pharmaceutically acceptable salt of each thereof, is administered concurrently or sequentially.

3. The method of claim 1 or 2, wherein the subject has previously received a CDK4 / 6 inhibitorbased therapy.

4. The method of any one of claims 1 to 3, wherein the breast cancer is CDK4 / 6 inhibitor resistant.

5. The method of any one of claims 1 to 4, wherein the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is about 100 mg or about 200 mg.

6. The method of any one of claims 1 to 5, wherein the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is about 200 mg.

7. The method of any one of claims 1 to 5, wherein the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is about 100 mg.

8. The method of any one of claims 1 to 7, wherein the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered once per day (QD).

9. The method of any one of claims 1 to 8, wherein the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is administered orally to the subject.

10. The method of any one of claims 1 to 9, wherein the subject is in a fed state.Attorney Docket No.: 100C-401885-WOARVN0205W0211. The method of any one of claims 1 to 10, wherein abemaciclib, or a pharmaceutically acceptable salt thereof, is administered to the subject.

12. The method of any one of claims 1 to 10, wherein ribociclib, or a pharmaceutically acceptable salt thereof, is administered to the subject.

13. The method of claim 11, wherein abemaciclib, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of about 150 mg twice daily.

14. The method of claim 11, wherein abemaciclib, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of about 100 mg twice daily.

15. The method of claim 11, wherein Compound A or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 200 mg once daily and abemaciclib, or a pharmaceutically acceptable salt thereof, is administered orally at a dose of about 150 mg twice daily.

16. The method of claim 11, wherein Compound A or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 100 mg once daily and abemaciclib, or a pharmaceutically acceptable salt thereof, is administered orally at a dose of about 150 mg twice daily.

17. The method of claim 11 , wherein Compound A or a pharmaceutical I y acceptable salt thereof is administered orally at a dose of about 200 mg once daily and abemaciclib, or a pharmaceutically acceptable salt thereof, is administered orally at a dose of about 100 mg twice daily.

18. The method of claim 11, wherein Compound A or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 100 mg once daily and abemaciclib, or a pharmaceutically acceptable salt thereof, is administered orally at a dose of about 100 mg twice daily.

19. The method of claim 12, wherein ribociclib, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of about 600 mg once daily.

20. The method of claim 12, wherein ribociclib, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose of about 400 mg once daily.

21. The method of claim 12, wherein Compound A or a pharmaceutically acceptable salt thereof is administered daily in 28-day cycles and ribociclib, or a pharmaceutically acceptable salt thereof, is administered orally at a daily dosage of about 600 mg once daily for 21 days followed by 7 days off treatment for each 28-day cycle.Attorney Docket No.: 100C-401885-WOARVN0205W0222. The method of claim 12, wherein Compound A or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 100 mg once daily and ribociclib, or a pharmaceutically acceptable salt thereof, is administered orally at a dose of about 600 mg once daily.

23. The method of claim 12, wherein Compound A or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 100 mg once daily and ribociclib, or a pharmaceutically acceptable salt thereof, is administered orally at a dose of about 400 mg once daily.

24. The method of claim 12, wherein Compound A or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 200 mg once daily and ribociclib, or a pharmaceutically acceptable salt thereof, is administered orally at a dose of about 600 mg once daily.

25. The method of claim 12, wherein Compound A or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 200 mg once daily and ribociclib, or a pharmaceutically acceptable salt thereof, is administered orally at a dose of about 400 mg once daily.

26. The method of any one of claims 1 to 25, wherein the ESRI mutation comprises Y537S.

27. The method of any one of claims 1 to 25, wherein the ESRI mutation comprises D538G.

28. The method of any one of claims 1 to 27, wherein the breast cancer is locally advanced or metastatic.

29. The method of any one of claims 1 to 27, wherein the breast cancer is metastatic.

30. The method of any one of claims 1 to 29, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer.

31. The method of claim 30, wherein the estrogen receptor positive (ER+) breast cancer is human epidermal growth factor receptor 2 negative (HER2-).

32. The method of claim 4, wherein the subject has previously received one or two lines of anticancer therapy, wherein one line of the one or two lines of anti-cancer therapy is the CDK4 / 6 inhibitor-based therapy.

33. The method of claim 4 or 32, wherein the subject has previously received one or two lines of anti-cancer therapy for the treatment of advanced and / or metastatic cancer, wherein one line of the one or two lines of anti-cancer therapy is the CDK4 / 6 inhibitor-based therapy.

34. The method of any one of claims 4, 32, and 33, wherein the subject has previously received a ribociclib, palbociclib, or abemaciclib in the CDK4 / 6 inhibitor-based therapy.Attorney Docket No.: 100C-401885-WOARVN0205W0235. The method of any one of claims 4 and 32 to 34, wherein the subject did not require a dose reduction due to an adverse event during the previous CDK4 / 6 inhibitor-based therapy.

36. The method of any one of claims 1 to 35, wherein the subject is human.

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