Elacestrant in combination with abemaciclib in women with breast cancer

Abstract

To provide elacestrant in combination with abemaciclib in women with breast cancer.SOLUTION: A method of treating breast cancer in a patient is provide, the method comprising administering to the patient a therapeutic combination comprising elacestrant or a pharmaceutically acceptable salt thereof, and abemaciclib or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross-reference to Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62 / 773,960, filed on Nov. 30, 2018. The entire contents of the foregoing application are hereby incorporated by reference herein in their entirety, including the drawings.

[0002] Technical Field of the Invention The present disclosure relates to a method of treating breast cancer in a patient, comprising the step of administering to the patient a therapeutic combination comprising elacestrant or a pharmaceutically acceptable salt thereof and abemaciclib or a pharmaceutically acceptable salt thereof. The present disclosure also relates to a method of treating breast cancer in a patient that results in a longer progression free survival time as compared to other treatments.

Background Art

[0003] Background of the Invention Resistance to endocrine therapy is a challenging aspect in the management of patients with estrogen receptor positive (ER+) breast cancer. Recent studies have shown that acquired resistance can occur after treatment with aromatase inhibitors through the emergence of mutations in the estrogen receptor 1 (ESR1) gene. Another mechanism associated with de novo and acquired resistance is the adaptive upregulation of parallel growth factor signaling pathways, as well as crosstalk between these pathways that promotes the expression of cyclin D1 and the activation of cyclin-dependent kinases 4 (CDK4) and 6 (CDK4 / 6).

[0004] Strategies designed to disrupt these mechanisms include combining inhibitors of the CDK4 / 6 pathway with endocrine therapy. Systemic effects were observed when such combination therapies were evaluated in preclinical studies using endocrine therapy-naive and endocrine therapy-resistant breast cancer cell lines. Furthermore, in the MONARCH-2 clinical trial, the combination of abemaciclib (a CDK4 / 6 inhibitor; Verzenio®, Eli Lilly and Company) and fulvestrant (the only approved selective estrogen receptor degrader [SERD]; Faslodex®, AstraZeneca) showed improved progression-free survival (PFS) compared to fulvestrant alone in patients with ER+ human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer.

[0005] Elacestrant (RAD1901) is a novel orally bioavailable SERD. Preclinical data indicate that elacestrant is effective in inhibiting tumor growth in both models of ER+ breast cancer with wild-type ESR1 and ER+ breast cancer with mutant ESR1, both as a single agent and in combination with a CDK4 / 6 inhibitor. Elacestrant monotherapy demonstrated antitumor activity in xenograft models derived from patients with ER+ breast cancer that were resistant to fulvestrant and harbored estrogen independence and / or ESR1 gene mutations. In multiple xenograft models of ER+ breast cancer, the combination of elacestrant and a CDK4 / 6 inhibitor showed greater antitumor activity than that observed with either drug alone.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] The object of the present invention is to provide elacestrant in combination with abemaciclib in women with breast cancer.

Means for Solving the Problems

[0008] That is, the gist of the present invention is as follows. Item 1 A method for treating breast cancer in a patient, comprising the step of administering to the patient a therapeutic combination comprising elacestrant or a pharmaceutically acceptable salt thereof and abemaciclib or a pharmaceutically acceptable salt thereof.

Effects of the Invention

[0009] According to the present invention, elacestrant in combination with abemaciclib in women with breast cancer can be provided.

Brief Description of the Drawings

[0010] Brief Description of the Drawings

Figure 1

Modes for Carrying Out the Invention

[0011] Summary of the Invention In one aspect, the present invention relates to a method for treating breast cancer in a patient, comprising the step of administering to the patient a therapeutic combination comprising elacestrant or a pharmaceutically acceptable salt thereof and abemaciclib or a pharmaceutically acceptable salt thereof.

[0012] In one embodiment of this aspect, the patient experiences a longer progression-free survival time compared to a patient administered a combination of letrozole and abemaciclib, a combination of anastrozole and abemaciclib, or a combination of fulvestrant and abemaciclib.

[0013] In another aspect of this situation, the patient experiences a greater progression-free survival time compared to a patient administered abemaciclib as monotherapy.

[0014] Detailed Description of the Invention As used herein, RAD1901 or "elacestrant" refers to the following structure including its salts, solvates (e.g., hydrates) and prodrugs:

Chemical Formula

[0015] In some aspects described herein, RAD1901 is administered as the bishydrochloride (·2HCl) salt.

[0016] As used herein, "abemaciclib" refers to the following structure including its salts, solvates (e.g., hydrates) and prodrugs:

Chemical Formula

[0017] Definitions As used herein, unless otherwise indicated, the following definitions apply.

[0018] As used herein, the terms "RAD1901" and "elacestrant" refer to the same compound and are used interchangeably.

[0019] "Inhibiting growth" of ERα-positive tumors, as used herein, may refer to delaying the rate of tumor growth or completely stopping tumor growth.

[0020] "Tumor regression" or "regression" of an ERα-positive tumor, as used herein, can refer to a reduction in the maximum size of the tumor. In certain embodiments, administration of the combinations or their solvates (e.g., hydrates) or salts described herein can result in a decrease in tumor size relative to baseline (i.e., the size prior to the start of treatment), or even eradication or partial eradication of the tumor. Thus, in certain embodiments, the methods of tumor regression provided herein can alternatively be characterized as methods of reducing tumor size relative to baseline.

[0021] "Tumor", as used herein, refers to a malignant tumor and is used interchangeably with "cancer".

[0022] "Estrogen receptor α" or "ERα", as used herein, refers to a polypeptide comprising, consisting of, or essentially consisting of the wild-type ERα amino acid sequence encoded by the gene ESR1.

[0023] A tumor that is "positive for estrogen receptor α", "ERα-positive", "ER+", or "ERα+" refers to a tumor in which one or more cells express at least one isoform of ERα.

[0024] Embodiment In one aspect, the present invention relates to a method of treating breast cancer in a patient, comprising administering to the patient a therapeutic combination comprising elacestrant or a pharmaceutically acceptable salt thereof and abemaciclib or a pharmaceutically acceptable salt thereof.

[0025] In one embodiment, the patient is a postmenopausal woman.

[0026] In another embodiment, the patient has not received prior therapy with a CDK4 / 6 inhibitor or a SERD.

[0027] In another embodiment, the breast cancer in the patient is progressing during prior endocrine therapy.

[0028] In another aspect, the breast cancer in the patient is ER+ breast cancer.

[0029] The method according to claim 5, wherein the breast cancer in the patient is HER2- breast cancer.

[0030] In another aspect, the breast cancer in the patient is advanced or metastatic breast cancer.

[0031] In one aspect, elacestrant is administered to the patient at a dose of 200 - 500 mg / day.

[0032] In a further aspect, elacestrant is administered to the patient at a dose of 250 - 450 mg / day.

[0033] In a further aspect, elacestrant is administered to the patient at a dose of about 300 mg / day.

[0034] In yet a further aspect, elacestrant is administered to the patient at a dose of about 300 mg / day once daily.

[0035] In another further aspect, elacestrant is administered to the patient at a dose of about 400 mg / day.

[0036] In yet a further aspect, elacestrant is administered to the patient at a dose of about 400 mg / day once daily.

[0037] In one aspect, abemaciclib is administered to the patient at a dose of 150 - 400 mg / day.

[0038] In a further aspect, abemaciclib is administered to the patient at a dose of about 200 mg / day.

[0039] In yet a further aspect, abemaciclib is administered to the patient at a dose of about 200 mg / day twice daily.

[0040] In another further aspect, abemaciclib is administered to a patient at a dose of about 100 mg twice a day.

[0041] In one aspect, abemaciclib is administered to a patient at a dose of about 300 mg / day.

[0042] In a further aspect, abemaciclib is administered to a patient at a dose of about 300 mg / day in two administrations per day.

[0043] In yet a further aspect, abemaciclib is administered to a patient at a dose of about 150 mg twice a day.

[0044] In one aspect, elacestrant is administered to a patient at a dose of about 400 mg / day, and abemaciclib is administered to a patient at a dose of about 300 mg / day.

[0045] In a further aspect, abemaciclib is administered to a patient at a dose of 150 mg twice a day.

[0046] In another aspect, elacestrant is administered to a patient at a dose of about 300 mg / day, and abemaciclib is administered to a patient at a dose of about 300 mg / day.

[0047] In a further aspect, abemaciclib is administered to a patient at a dose of 150 mg twice a day.

[0048] In another aspect, elacestrant is administered to a patient at a dose of about 300 mg / day, and abemaciclib is administered to a patient at a dose of about 200 mg / day.

[0049] In a further aspect, abemaciclib is administered to a patient at a dose of 100 mg twice a day.

[0050] In one aspect, elacestrant is administered to a patient at the maximum allowable dose for the patient.

[0051] In one aspect, abemaciclib is administered to a patient at a dose that is the maximum tolerated dose for the patient.

[0052] In one aspect of this scenario, the patient experiences a greater progression-free survival time compared to a patient administered a combination of letrozole and abemaciclib, a combination of anastrozole and abemaciclib, or a combination of fulvestrant and abemaciclib.

[0053] In a further aspect, the breast cancer is ER+ / HER2- advanced or metastatic breast cancer, and the patient has progressed during or after previous adjuvant or metastatic endocrine therapy and has not received previous treatment with a CDK4 / 6 inhibitor or SERD.

[0054] In one aspect, patients administered a combination of letrozole and abemaciclib were administered 2.5 mg of letrozole once daily and 125 mg of abemaciclib twice daily.

[0055] In another aspect, patients administered a combination of anastrozole and abemaciclib were administered 1 mg of anastrozole once daily and 125 mg of abemaciclib twice daily.

[0056] In another aspect, patients administered a combination of fulvestrant and abemaciclib were administered 500 mg of fulvestrant as two 5 mL intramuscular injections into the gluteal region (buttock area) at a rate of 1 to 2 minutes per injection, once in each buttock, on days 1, 15, and 29 and then monthly thereafter, and 125 mg of abemaciclib twice daily.

[0057] In another aspect, the patient experiences a greater progression-free survival time compared to a patient administered a combination of letrozole and abemaciclib, the breast cancer is ER+ / HER2− advanced or metastatic breast cancer, the patient has not received prior systemic anti-cancer therapy for that advanced / metastatic disease, and has not received prior treatment with a CDK4 / 6 inhibitor or SERD.

[0058] In a further aspect, patients administered a combination of letrozole and abemaciclib were administered 2.5 mg of letrozole once daily and 125 mg of abemaciclib twice daily.

[0059] In another aspect of this scenario, the patient experiences a greater progression-free survival time compared to a patient administered abemaciclib as monotherapy.

[0060] In a further aspect, the breast cancer is ER+ / HER2− advanced or metastatic breast cancer, the patient has received prior systemic anti-cancer therapy including ≤2 prior chemotherapy for metastatic breast cancer permitted for that advanced or metastatic disease, and the prior systemic anti-cancer therapy did not include a CDK4 / 6 inhibitor or SERD.

[0061] In yet a further aspect, patients administered abemaciclib as monotherapy were administered 200 mg of abemaciclib twice daily.

[0062] Formulation, Administration and Use Combination therapies comprising elacestrant and a CDK inhibitor are described in U.S. Patent Application Publication No. 2018 / 0169101, the entire contents of which are incorporated herein by reference in their entirety.

[0063] A combination of RAD1901 or a solvate (e.g., hydrate) or salt thereof and abemaciclib Both RAD1901 or a solvate (e.g., hydrate) or salt thereof and abemaciclib have a therapeutic effect on one or more cancers or tumors when administered alone to a subject. Surprisingly, when administered in combination to a subject, it has been discovered that RAD1901 or a solvate (e.g., hydrate) or salt thereof and abemaciclib have a significantly improved effect on the cancer / tumor.

[0064] Tumor growth inhibition or regression can be localized to a single tumor or group of tumors within a particular tissue or organ, or can be systemic (i.e., affecting tumors in all tissues or organs).

[0065] Since RAD1901 is known to preferentially bind to estrogen receptor beta (ERβ) over ERα, estrogen receptor, estrogen receptor alpha, ERα, ER, wild-type ERα, and ESR1 are used interchangeably herein unless specified otherwise. In certain embodiments, ER+ cells overexpress ERα. In certain embodiments, a patient has one or more cells within a tumor that expresses one or more forms of ERβ. In certain embodiments, ERα-positive tumors and / or cancers are associated with breast cancer, uterine cancer, ovarian cancer, or pituitary cancer. In some of these embodiments, the patient has a tumor located in breast, uterine, ovarian, or pituitary tissue. In these embodiments where the patient has a tumor located in the breast, the tumor may be associated with luminal breast cancer, which may or may not be positive for HER2, and for HER2+ tumors, the tumor may over- or under-express HER2. In other embodiments, the patient has a tumor located in another tissue or organ (e.g., bone, muscle, brain), but is nevertheless associated with breast cancer, uterine cancer, ovarian cancer, or pituitary cancer (e.g., a tumor resulting from metastasis or spread of breast cancer, uterine cancer, ovarian cancer, or pituitary cancer). Thus, in certain embodiments of the tumor growth inhibition or tumor regression methods provided herein, the targeted tumor is a metastatic tumor and / or the tumor has overexpression of ER in another organ (e.g., bone and / or muscle). In certain embodiments, the targeted tumor is a brain tumor and / or cancer.In one aspect, the tumor to be targeted is more sensitive to treatment with RAD1901 and abemaciclib than treatment with another SERD (e.g., fulvestrant, TAS-108 (SR16234), ZK191703, RU58668, GDC-0810 (ARN-810), GW5638 / DPC974, SRN-927, ICI182782, and AZD9496), a Her2 inhibitor (e.g., trastuzumab, lapatinib, ado-trastuzumab emtansine, and / or pertuzumab), chemotherapy (e.g., abraxane, doxorubicin, carboplatin, cytoxan, daunorubicin, doxil, ellence, fluorouracil, gemzar, helaven, lxempra, methotrexate, mitomycin, mitoxantrone, navelbine, taxol, taxotere, thiotepa, vincristine, and xeloda), an aromatase inhibitor (e.g., anastrozole, exemestane, and letrozole), a selective estrogen receptor modulator (e.g., tamoxifen, raloxifene, lasofoxifene, and / or toremifene), an angiogenesis inhibitor (e.g., bevacizumab), and / or rituximab.

[0066] In certain embodiments of the tumor growth inhibition or tumor regression methods provided herein, the method further comprises determining whether the patient has tumors that express ERα prior to administering abemaciclib in combination with RAD1901 or a solvate (e.g., hydrate) or salt thereof. In certain embodiments of the tumor growth inhibition or tumor regression methods provided herein, the method further comprises determining whether the patient has tumors that express mutant ERα prior to administering abemaciclib in combination with RAD1901 or a solvate (e.g., hydrate) or salt thereof. In certain embodiments of the tumor growth inhibition or tumor regression methods provided herein, the method further comprises determining whether the patient has tumors that express ERα that are responsive or non-responsive to fulvestrant treatment prior to administering abemaciclib in combination with RAD1901 or a solvate (e.g., hydrate) or salt thereof. These determinations can be made using any expression detection method known in the art and can be performed in vitro using tumor or tissue samples removed from the subject.

[0067] In addition to showing the ability to inhibit tumor growth in tumors that express wild-type ERα, RAD1901 shows an unexpected ability to inhibit the growth of tumors that express a mutant form of ERα, namely Y537S ERα. Computer modeling evaluations of examples of ERα mutations have shown that ERα having one or more mutants selected from the group consisting of these mutations, such as ERα having a Y537X mutant (where X is S, N, or C), ERα having a D538G mutant, and ERα having an S463P mutant, are not predicted to affect the LBD or specifically interfere with RAD1901 binding. Based on these results, by administering to a subject having cancer a therapeutically effective amount of abemaciclib in combination with RAD1901 or a solvate (e.g., hydrate) or salt thereof, in a subject having cancer, for the purpose of inhibiting the growth or causing regression of tumors that are positive for ERα having one or more mutants selected from the group consisting of Y537X1 (where X1 is S, N, or C), D538G, L536X2 (where X2 is R or Q), P535H, V534E, S463P, V392I, E380Q in the ligand binding domain (LBD), particularly Y537S ERα, a method is provided herein. In certain embodiments, RAD1901 or a solvate (e.g., hydrate) or salt thereof. "Mutant ERα" as used herein refers to ERα containing one or more substitutions or deletions, and variants thereof that contain, consist of, or consist essentially of an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 99.5% identity to the amino acid sequence of ERα.

[0068] In addition to inhibiting breast cancer tumor growth in an animal xenograft model, RAD1901 shows significant accumulation within tumor cells and can cross the blood-brain barrier. The ability to cross the blood-brain barrier was confirmed by showing that RAD1901 administration significantly extends survival in a brain metastasis xenograft model. Thus, in certain aspects of the tumor growth inhibition or tumor regression methods provided herein, the targeted ERα-positive tumors are located in the brain or other locations within the central nervous system. In some of these aspects, the ERα-positive tumors are primarily associated with brain cancer. In other aspects, the ERα-positive tumors are metastatic tumors primarily associated with another type of cancer, such as breast cancer, uterine cancer, ovarian cancer, or pituitary cancer, or tumors that have migrated from another tissue or organ. In some of these aspects, the tumors are brain metastases, such as breast cancer brain metastases (BCBM). In certain aspects of the methods disclosed herein, RAD1901 or a solvate (e.g., hydrate) or salt thereof accumulates within one or more cells within the target tumor.

[0069] In certain aspects of the methods disclosed herein, RAD1901 or a solvate (e.g., hydrate) or salt thereof preferably accumulates in the tumor at a T / P (tumor RAD1901 concentration / plasma RAD1901 concentration) ratio of about 15 or greater, about 18 or greater, about 19 or greater, about 20 or greater, about 25 or greater, about 28 or greater, about 30 or greater, about 33 or greater, about 35 or greater, or about 40 or greater.

[0070] The results showed that RAD1901 administration protected against bone loss in ovariectomized rats. Thus, in certain aspects of the tumor growth inhibition or tumor regression methods provided herein, administration of abemaciclib in combination with RAD1901 or a solvate (e.g., hydrate) or salt thereof does not have an undesirable effect on bone, such as an undesirable effect on bone volume density, bone surface density, bone mineral density, trabecular number, trabecular width, trabecular separation, connectivity density, and / or apparent bone density of a subject being treated. Tamoxifen may be associated with bone loss in premenopausal women, and fulvestrant may impair bone structure due to its mechanism of action. Thus, the combination of abemaciclib and RAD1901 or a solvate (e.g., hydrate) or salt thereof may be particularly useful for premenopausal women, tumors resistant to tamoxifen or antiestrogen therapy, and patients with osteoporosis and / or a high risk of osteoporosis.

[0071] RAD1901 has been shown to antagonize estradiol stimulation of uterine tissue in ovariectomized rats. Further, in human subjects treated with RAD1901 at doses up to 200 mg or 500 mg per day (q.d.), the standardized uptake value (SUV) for uterine, muscle, and bone tissue that did not significantly express ER showed little to no change in symptoms before and after treatment. Thus, in certain aspects, such administration also does not produce an undesirable effect on other tissues, such as uterine, muscle, or breast tissue.

[0072] RAD1901 or a solvate (e.g., hydrate) or salt thereof and abemaciclib are administered in combination to a subject in need thereof. The phrase "in combination" means that RAD1901 or a solvate (e.g., hydrate) or salt thereof can be administered before, during, or after the administration of abemaciclib. For example, RAD1901 or a solvate (e.g., hydrate) or salt thereof and abemaciclib can be administered about 1 week apart, about 6 days apart, about 5 days apart, about 4 days apart, about 3 days apart, about 2 days apart, about 24 hours apart, about 23 hours apart, about 22 hours apart, about 21 hours apart, about 20 hours apart, about 19 hours apart, about 18 hours apart, about 17 hours apart, about 16 hours apart, about 15 hours apart, about 14 hours apart, about 13 hours apart, about 12 hours apart, about 11 hours apart, about 10 hours apart, about 9 hours apart, about 8 hours apart, about 7 hours apart, about 6 hours apart, about 5 hours apart, about 4 hours apart, about 3 hours apart, about 2 hours apart, about 1 hour apart, about 55 minutes apart, about 50 minutes apart, about 45 minutes apart, about 40 minutes apart, about 35 minutes apart, about 30 minutes apart, about 25 minutes apart, about 20 minutes apart, about 15 minutes apart, about 10 minutes apart, or about 5 minutes apart. In other embodiments, RAD1901 or a solvate (e.g., hydrate) or salt thereof and abemaciclib are administered to the subject simultaneously or substantially simultaneously. In some of these embodiments, RAD1901 or a solvate (e.g., hydrate) or salt thereof and abemaciclib can be administered as part of a single formulation.

[0073] Dosage The therapeutically effective amount of abemaciclib and RAD1901 or a solvate (e.g., hydrate) or salt thereof in combination for use in the methods disclosed herein is an amount that, when administered over a particular time interval, results in the achievement of one or more treatment benchmarks (e.g., delay or arrest of tumor growth, occurrence of tumor regression, remission of symptoms, etc.). The combination for use in the methods disclosed herein can be administered to a subject one or more times. In these embodiments where the compounds are administered multiple times, the compounds can be administered at regular intervals, such as daily, every other day, weekly, or monthly. Alternatively, the compounds can be administered on an as-needed basis at irregular intervals, e.g., based on symptoms, the health status of the patient, etc. The therapeutically effective amount of the combination can be administered daily for a period of 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 10 days, or at least 15 days. Optionally, the cancer status or tumor regression is monitored by FES-PET scan of the subject during or after treatment. The dosage of the combination administered to the subject can be increased or decreased depending on the detected cancer status or tumor regression.

[0074] Ideally, the therapeutically effective amount does not exceed the maximum tolerated dose at which 50% or more of the treated subjects experience nausea or other toxic reactions that interfere with further drug administration. The therapeutically effective amount can vary for a subject depending on various factors including the variety and degree of the subject's symptoms, gender, age, weight or general health status, mode of administration, and type of salt or solvate, variation in sensitivity to the drug, the particular type of disease, etc.

[0075] Examples of a therapeutically effective amount of RAD1901 or a solvate (e.g., hydrate) or salt thereof for use in the methods disclosed herein include, without limitation, about 150 to about 1,500 mg, about 200 to about 1,500 mg, about 250 to about 1,500 mg, or about 300 to about 1,500 mg per day at a dose for a subject having a resistant ER-derived tumor or cancer; about 150 to about 1,500 mg, about 200 to about 1,000 mg, about 250 to about 1,000 mg, or about 300 to about 1,000 mg per day at a dose for a subject having both wild-type ER-derived tumors and / or cancers and resistant tumors and / or cancers; and about 300 to about 500 mg, about 300 to about 550 mg, about 300 to about 600 mg, about 250 to about 500 mg, about 250 to about 550 mg, about 250 to about 600 mg, about 200 to about 500 mg, about 200 to about 550 mg, about 200 to about 600 mg, about 150 to about 500 mg, about 150 to about 550 mg, or about 150 to about 600 mg per day at a dose for a subject having predominantly wild-type ER-derived tumors and / or cancers. In certain embodiments, the dose of a compound of Formula I (e.g., RAD1901) or a salt or solvate thereof for use in the methods disclosed herein that is typical for an adult subject can be about 200 mg, 400 mg, 30 mg to 2,000 mg, 100 mg to 1,500 mg, or 150 mg to 1,500 mg orally, per day. This daily dose can be achieved by a single administration or multiple administrations.

[0076] Administration of RAD1901 together with abemaciclib can be achieved using RAD1901 at 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1,000 mg per day. In particular, 200 mg, 400 mg, 500 mg, 600 mg, 800 mg and 1,000 mg per day are noted. In certain circumstances, a twice-daily dosing schedule is preferred. Surprisingly, the long half-life of RAD1901 in humans after PO administration makes this option particularly realistic. Thus, the drug can be administered as 200 mg twice a day (400 mg total per day), 250 mg twice a day (500 mg total per day), 300 mg twice a day (600 mg total per day), 400 mg twice a day (800 mg per day) or 500 mg twice a day (1,000 mg total per day). Preferably, the administration is oral. The dose of abemaciclib can be 50 mg to 500 mg per day or 150 mg to 450 mg per day, and the administration can be daily in a 28-day cycle or less than 28 days per 28-day cycle, for example 21 days per 28-day cycle or 14 days per 28-day cycle or 7 days per 28-day cycle. In some embodiments, abemaciclib is administered once a day or preferably, on a twice-daily schedule, and the administration is oral. In the case of twice-daily administration, the doses can be separated by 4 hours, 8 hours or 12 hours. In one embodiment, abemaciclib is administered orally at 150 mg twice a day, where the administration is preferably spaced 12 hours apart.

[0077] As discovered, a significant synergistic effect is seen between RAD1901 and a CDK 4 / 6 inhibitor, and thus a dose reduction of RAD1901 and / or abemaciclib from the normal recommended or approved doses is contemplated. For example, RAD1901 may be recommended for single-agent treatment at a dose of 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg or more per day, particularly at 200 mg, 400 mg, 500 mg, 600 mg, 800 mg and 1000 mg. In combination, a specific dose reduction by a given fraction means that doses 25% to 75% less than the normal dose are possible. As a non-limiting example, the recommended dose of RAD1901 at 400 mg per day can be reduced to a final dose of 100 mg to 300 mg per day or 100 mg per day, 200 mg per day or 300 mg per day. When the RAD1901 dose is reduced as described, the same percent reduction generally applies whether the administration is twice daily or once daily. For example, a 400 mg twice-daily dose reduced by 50% is administered on a 200 mg twice-daily schedule. In some exceptions, a reduction of the recommended twice-daily dose per day may be sufficient to allow the total daily dose to be administered as a once-daily dose. For example, the normal 300 mg twice-daily dose given in combination with abemaciclib can be reduced by 50%. Thus, the dose can be given as 150 mg twice-daily or 300 mg once-daily.

[0078] Similarly, the normal recommended dosage of abemaciclib can be reduced when used in combination with RAD1901. The dosage of abemaciclib can be reduced and combined with the normal recommended single-therapy dosage of RAD1901 or a reduced RAD1901 dosage, where the reduced dosage is 25% to 75% less than the normal recommended dosage as exemplified just above. For example, the recommended dosage of abemaciclib at 150 mg twice daily can be given as a twice-daily dosage that is 25% to 75% less than the 150 mg twice-daily dosage. For example, 150 mg of abemaciclib twice daily can be reduced to a twice-daily dosage of 37.5 mg to 112.5 mg (total daily dosage of 75 mg to 225 mg). Alternatively, it may be desirable to reduce the frequency of abemaciclib from the recommended 28-day cycle to some lesser frequency. For example, the dosing frequency can be reduced to 22 to 27 days out of a 28-day cycle or to 21 days out of a 28-day cycle, or the dosing frequency can be reduced to 15 to 20 days out of a 28-day cycle or to 14 days out of a 28-day cycle, or the dosing frequency can be reduced to 8 to 13 days out of a 28-day cycle or to exactly 7 days out of a 28-day cycle. The days of administration can be consecutive or combined if necessary in this situation. In one aspect, the total dosage over the dosing interval is reduced by 25% to 75% of the recommended dosage, and such reduction can occur as a result of less frequent dosing, reduced dosage, or a combination thereof. For example, the recommended 28-day dosing cycle of abemaciclib at a dosage of 150 mg twice daily (300 mg total daily) results in a total dosage of 8,400 mg over 28 days (28 days at 300 mg per day total). This amount can be reduced to 2,100 mg per 28 days to 6,300 mg per 28 days.

[0079] In certain embodiments, the therapeutically effective amount of the combination can utilize the therapeutically effective amount of any of the compounds administered alone. In other embodiments, due to the significantly improved synergistic therapeutic effect achieved by the combination, the therapeutically effective amount of RAD1901 or a solvate (e.g., hydrate) or salt thereof and abemaciclib, when administered in combination, may be less than the therapeutically effective amount of RAD1901 or a solvate (e.g., hydrate) or salt thereof and abemaciclib required when administered alone; one or both compounds may be administered at a lower dose than the dose at which they are typically administered when given separately. Without being bound by any particular theory, the combination therapy achieves a significantly improved effect by reducing at least one or all of the doses of RAD1901 or a solvate (e.g., hydrate) or salt thereof and abemaciclib to eliminate or reduce undesirable toxic side effects.

[0080] In some embodiments, when administered as part of a combination, the therapeutically effective amount of RAD1901 or a solvate (e.g., hydrate) or salt thereof is about 30% to about 200%, about 40% to about 200%, about 50% to about 200%, about 60% to about 200%, about 70% to about 200%, about 80% to about 200%, about 90% to about 200%, about 100% to about 200%, 30% to about 150%, about 40% to about 150%, about 50% to about 150%, about 60% to about 150%, about 70% to about 150%, about 80% to about 150%, about 90% to about 150%, about 100% to about 150%, about 30% to about 120%, about 40% to about 120%, about 50% to about 120%, about 60% to about 120%, about 70% to about 120%, about 80% to about 120%, about 90% to about 120%, about 100% to about 120%, 30% to about 110%, about 40% to about 110%, about 50% to about 110%, about 60% to about 110%, about 70% to about 110%, about 80% to about 110%, about 90% to about 110% or about 100% to about 110% of the therapeutically effective amount of RAD1901 or a solvate (e.g., hydrate) or salt thereof when administered alone. In some embodiments, when administered as part of a combination, the therapeutically effective amount of abemaciclib is about 30% to about 200%, about 40% to about 200%, about 50% to about 200%, about 60% to about 200%, about 70% to about 200%, about 80% to about 200%, about 90% to about 200%, about 100% to about 200%, 30% to about 150%, about 40% to about 150%, about 50% to about 150%, about 60% to about 150%, about 70% to about 150%, about 80% to about 150%, about 90% to about 150%, about 100% to about 150%, about 30% to about 120%, about 40% to about 120%, about 50% to about 120%, about 60% to about 120%, about 70% to about 120%, about 80% to about 120%, about 90% to about 120%, about 100% to about 120%, 30% to about 110%, about 40% to about 110%, about 50% to about 110%, about 60% to about 110%, about 70% to about 110%, about 80% to about 110%, about 90% to about 110% or about 100% to about 110% of the therapeutically effective amount of abemaciclib when administered alone.

[0081] In certain embodiments, the cancer or tumor is a resistant ER-derived cancer or tumor (e.g., an ERα having one or more mutations including, but not limited to, a mutant ER binding domain such as Y537X1 (where X1 is S, N or C), D538G, L536X2 (where X2 is R or Q), P535H, V534E, S463P, V392I, E380Q and combinations thereof), an overexpressor of ER or a tumor and / or cancer growth that becomes ligand-dependent, or another SERD (e.g., fulvestrant, TAS-108 (SR16234), ZK191703, RU58668, GDC-0810 (ARN-810), GW5638 / DPC974, SRN-927, ICI182782 and AZD9496), a Her2 inhibitor (e.g., trastuzumab, lapatinib, ado-trastuzumab emtansine and / or pertuzumab), chemotherapy (e.g., abraxane, adriamycin, carboplatin, cytoxan, daunorubicin, doxil, elence, fluorouracil, gemzar, heraven, luxempra, methotrexate, mitomycin, mitoxantrone, navelbine, taxol, taxotere, thiotepa, vincristine and xeloda), an aromatase inhibitor (e.g., anastrozole, exemestane and letrozole), a selective estrogen receptor modulator (e.g., tamoxifen, raloxifene, lasofoxifene and / or toremifene), an angiogenesis inhibitor (e.g., bevacizumab) and / or a tumor and / or cancer that progresses with treatment with rituximab).

[0082] In certain embodiments, the dosage of RAD1901 or a solvate (e.g., hydrate) or salt thereof in combination with abemaciclib for use in the methods disclosed herein generally for adult subjects can be about 30 mg to 2,000 mg, 100 mg to 1,500 mg or 150 mg to 1,500 mg orally, daily. This daily dosage can be achieved by a single administration or multiple administrations.

[0083] Abemaciclib and RAD1901 or a solvate (e.g., hydrate) or salt thereof may be administered to a subject one or more times. In these embodiments where the compounds are administered multiple times, the compounds may be administered at specified intervals, such as daily, every other day, weekly, or monthly. Alternatively, the compounds may be administered on an as-needed basis at irregular intervals, e.g., based on symptoms, the patient's health status, etc.

[0084] Formulation In some embodiments, RAD1901 or a solvate (e.g., hydrate) or salt thereof and abemaciclib are administered in separate formulations. In some of these embodiments, the formulations may be of the same type. For example, both formulations may be designed for oral administration (e.g., by two separate pills) or for injection (e.g., by two separate injectable formulations). In other embodiments, RAD1901 or a solvate (e.g., hydrate) or salt thereof and abemaciclib may be formulated in different types of formulations. For example, one compound may be in a formulation designed for oral administration and the other may be in a formulation designed for injection.

[0085] In other embodiments, RAD1901 or a solvate (e.g., hydrate) or salt thereof and abemaciclib are administered as part of a single formulation. For example, RAD1901 or a solvate (e.g., hydrate) or salt thereof and abemaciclib may be formulated in a single pill for oral administration or in a single dose for injection. In one embodiment, a combination formulation comprising RAD1901 or a solvate (e.g., hydrate) or salt thereof and abemaciclib is provided herein. In one embodiment, administration of the compounds in a single formulation improves patient compliance.

[0086] When administered in combination, the therapeutically effective amount of each compound may be lower than the therapeutically effective amount of each compound when administered alone.

[0087] In some embodiments, a formulation comprising RAD1901 or a solvate (e.g., hydrate) or salt thereof, abemaciclib, or both RAD1901 or a solvate (e.g., hydrate) or salt thereof and abemaciclib may further comprise one or more pharmaceutical excipients, carriers, adjuvants, and / or preservatives.

[0088] RAD1901 or a solvate (e.g., hydrate) or salt thereof and abemaciclib for use in the methods disclosed herein can be formulated into unit dosage forms that mean physically discrete units suitable as unit doses for a subject being treated, wherein each unit contains a predetermined quantity of the active material calculated to produce the desired therapeutic effect, optionally together with a suitable pharmaceutical carrier. The unit dosage forms can be for one of a single daily dose or multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage forms can be the same or different for each administration. In some embodiments, the compounds can be formulated for controlled release.

[0089] RAD1901 or a solvate (e.g., hydrate) or salt thereof, and abemaciclib for use in the methods disclosed herein can be formulated according to any available conventional method. Examples of preferred dosage forms include tablets, powders, fine granules, granules, coated tablets, capsules, syrups, troches, inhalants, suppositories, injectable substances, ointments, ophthalmic ointments, eye drops, nasal drops, ear drops, poultices, lotions, etc. In formulation, generally used additives such as diluents, binders, disintegrants, lubricants, colorants, flavoring and odor-correcting agents, and, if necessary, stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives, antioxidants, etc. can be used. Also, formulation is made by combining compositions generally used as raw materials for pharmaceutical preparations according to conventional methods. Examples of these compositions include, for example, (1) oils such as soybean oil, beef tallow, and synthetic glycerides; (2) hydrocarbons such as liquid paraffin, squalane, and solid paraffin; (3) ester oils such as octyldodecyl myristate and isopropyl myristate; (4) higher alcohols such as cetostearyl alcohol and behenyl alcohol; (5) silicone resins; (6) silicone oils; (7) surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, solid polyoxyethylene castor oil, and polyoxyethylene polyoxypropylene block copolymers; (8) water-soluble macromolecules such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinyl pyrrolidone, and methyl cellulose; (9) lower alcohols such as ethanol and isopropanol; (10) polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol, and sorbitol; (11) sugars such as glucose and sucrose; (12) inorganic powders such as anhydrous silicic acid, aluminum magnesium silicate, and aluminum silicate; (13) purified water, etc.Additives for use in the above formulation include, for example: 1) lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, and silicon dioxide as diluents; 2) polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polypropylene glycol-polyoxyethylene block copolymer, meglumine, calcium citrate, dextrin, pectin, etc. as binders; 3) starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, carboxymethyl cellulose / calcium, etc. as disintegrants; 4) magnesium stearate, talc, polyethylene glycol, silica, condensed plant oil, etc. as lubricants; 5) any colorant whose addition is pharmaceutically acceptable as a colorant; 6) cocoa powder, menthol, aromatizer, peppermint oil, cinnamon powder as flavoring and odor-correcting agents; 7) antioxidants such as ascorbic acid or alpha tophenol, whose addition is pharmaceutically acceptable.

[0090] Abemaciclib and RAD1901 or a solvate (e.g., hydrate) or salt thereof for use in the methods disclosed herein may be formulated into a pharmaceutical composition as any one or more of the active compounds described herein and a physiologically acceptable carrier (also referred to as a pharmaceutically acceptable carrier or solution or diluent). Such carriers and solutions include salts and solvates of pharmaceutically acceptable compounds used in the methods of the present invention, as well as mixtures containing two or more of such compounds, pharmaceutically acceptable salts of the compounds, and solvates of pharmaceutically acceptable compounds. Such compositions are prepared according to acceptable pharmaceutical procedures such as those described in Remington's Pharmaceutical Sciences, 17th Edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Eaton, Pa. (1985), which is incorporated herein by reference.

[0091] The term "pharmaceutically acceptable carrier" refers to a carrier that does not cause an allergic reaction or other adverse effects in the patient to whom it is administered and is compatible with the other components in the formulation. Pharmaceutically acceptable carriers include, for example, pharmaceutically acceptable diluents, excipients or carriers appropriately selected with respect to the intended dosage form and not inconsistent with conventional pharmaceutical practice. For example, solid carriers / diluents include, but are not limited to, rubber, starch (e.g., corn starch, pregelatinized starch), sugars (e.g., lactose, mannitol, sucrose, dextrose), cellulosic materials (e.g., microcrystalline cellulose), acrylates (e.g., polymethyl acrylate), calcium carbonate, magnesium oxide, talc or mixtures thereof. Pharmaceutically acceptable carriers may further contain minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffering agents that enhance the shelf life or effectiveness of the therapeutic agent.

[0092] The free form of abemaciclib and RAD1901 or its solvate (e.g., hydrate) or salt can be converted to a salt by conventional methods. As used herein, the term "salt" is formed with RAD1901 or its solvate (e.g., hydrate) or salt and is not limited as long as it is pharmaceutically acceptable; preferred examples of salts include hydrohalides (e.g., hydrogen chloride, hydrogen bromide, hydrogen iodide, etc.), inorganic acid salts (e.g., sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, etc.), organic carboxylates (e.g., acetate, maleate, tartrate, fumarate, citrate, etc.), organic sulfonates (e.g., methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate, etc.), amino acid salts (e.g., aspartate, glutamate, etc.), quaternary ammonium salts, alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (magnesium salt, calcium salt, etc.), and the like. Also, hydrochloride, sulfate, methanesulfonate, acetate, etc. are preferred as "pharmaceutically acceptable salts" of the compounds according to the present invention.

[0093] RAD1901 or its solvate (e.g., hydrate) or salt and / or isomers of abemaciclib (e.g., geometric isomers, optical isomers, rotamers, tautomers, etc.) can be purified to a single isomer using common separation means including, for example, recrystallization, optical resolution such as the diastereomeric salt method, enzyme fractionation method, and various chromatographies (e.g., thin layer chromatography, column chromatography, glass chromatography, etc.). As used herein, the term "single isomer" includes not only isomers having 100% purity but also isomers containing non-target isomers that also exist through conventional purification operations. For RAD1901 or its solvate (e.g., hydrate) or salt and / or abemaciclib, crystal polymorphs sometimes exist, and all of these crystal polymorphs are included in the present invention. The crystal polymorphs are sometimes single and sometimes a mixture, and both are included in the present invention.

[0094] In certain embodiments, RAD1901 or a solvate (e.g., hydrate) or salt thereof and / or abemaciclib can be in the form of a prodrug, meaning that it must undergo some change (e.g., oxidation or hydrolysis) to achieve its active form. Alternatively, RAD1901 or a solvate (e.g., hydrate) or salt thereof and / or abemaciclib can be a compound produced by the change of a parent prodrug to its active form.

[0095] Route of administration Routes of administration of RAD1901 or a solvate (e.g., hydrate) or salt thereof and / or abemaciclib include, but are not limited to, topical administration, oral administration, intradermal administration, intramuscular administration, intraperitoneal administration, intravenous administration, intracapsular administration, subcutaneous administration, transdermal administration, and transmucosal administration.

[0096] Gene profiling In certain aspects, the methods of tumor growth inhibition or tumor regression provided herein further include the step of genetically profiling a subject, where the genes to be profiled are one or more genes selected from the group consisting of ABL1, AKT1, AKT2, ALK, APC, AR, ARID1A, ASXL1, ATM, AURKA, BAP, BAP1, BCL2L11, BCR, BRAF, BRCA1, BRCA2, CCND1, CCND2, CCND3, CCNE1, CDH1, CDK4, CDK6, CDK8, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CEBPA, CTNNB1, DDR2, DNMT3A, E2F3, EGFR, EML4, EPHB2, ERBB2, ERBB3, ESR1, EWSR1, FBXW7, FGF4, FGFR1, FGFR2, FGFR3, FLT3, FRS2, HIF1A, HRAS, IDH1, IDH2, IGF1R, JAK2, KDM6A, KDR, KIF5B, KIT, KRAS, LRP1B, MAP2K1, MAP2K4, MCL1, MDM2, MDM4, MET, MGMT, MLL, MPL, MSH6, MTOR, MYC, NF1, NF2, NKX2-1, NOTCH1, NPM, NRAS, PDGFRA, PIK3CA, PIK3R1, PML, PTEN, PTPRD, RARA, RB1, RET, RICTOR, ROS1, RPTOR, RUNX1, SMAD4, SMARCA4, SOX2, STK11, TET2, TP53, TSC1, TSC2, and VHL.

[0097] In some aspects, the present invention provides a method of treating a subpopulation of breast cancer patients, where the subpopulation has increased expression of one or more of the above-described genes, and the method comprises treating the subpopulation with an effective dose of abemaciclib in combination with RAD1901 or a solvate (e.g., hydrate) or salt thereof, according to the dosing regimens described herein.

[0098] Dose adjustment In addition to establishing the ability of RAD1901 to inhibit tumor growth, RAD1901 inhibits the binding of estradiol to ER in the uterus and pituitary gland. In these experiments, estradiol that binds to ER in uterine and pituitary tissues was evaluated by FES-PET imaging. After treatment with RAD1901, the observed levels of ER binding were below background levels. These results establish that the antagonist effect of RAD1901 on ER activity can be evaluated using real-time scanning. Based on these results, a method is provided herein for monitoring the efficacy of therapeutic RAD1901 or its solvate (e.g., hydrate) or salt in the combination therapies disclosed herein by measuring estradiol-ER binding in one or more target tissues, where a decrease or loss of binding indicates efficacy.

[0099] Based on estradiol-ER binding, a method is further provided for adjusting the dosage of RAD1901 or its solvate (e.g., hydrate) or salt in the combination therapies disclosed herein. In certain embodiments of these methods, binding is measured at several points after one or more administrations of a first dosage of the compound. If estradiol-ER binding is not affected or shows a decrease below a predetermined threshold (e.g., a decrease in binding of less than 5%, less than 10%, less than 20%, less than 30%, or less than 50% relative to baseline), the first dosage is presumed to be too low. In certain embodiments, these methods include a further step of administering an increased second dosage of the compound. These steps may be repeated, and the dosage is repeatedly increased until the desired reduction in estradiol-ER binding is achieved. In certain embodiments, these steps may be incorporated into the methods for inhibiting tumor growth provided herein. In these methods, estradiol-ER binding may function as a surrogate for tumor growth inhibition or as an adjunct means of assessing growth inhibition. In other embodiments, these methods may be used in combination with the administration of RAD1901 or its solvate (e.g., hydrate) or salt for purposes other than inhibition of tumor growth, such as inhibition of cancer cell proliferation.

[0100] In one aspect, the methods provided herein for adjusting the dosage of RAD1901 or a salt or solvate thereof (e.g., hydrate) in a combination therapy are: (1) administering a first dosage of RAD1901 or a salt or solvate thereof (e.g., hydrate) (e.g., about 350 to about 500 or about 200 to about 600 mg / day) for 3, 4, 5, 6, or 7 days; (2) detecting estradiol-ER binding activity; wherein: (i) if the ER binding activity is not detectable or is below a predetermined threshold level, continue administering the first dosage (i.e., maintain the dosage level); or (ii) if the ER binding activity is detectable or is higher than a predetermined threshold level, administer a second dosage higher than the first dosage (e.g., the first dosage + about 50 to about 200 mg) for 3, 4, 5, 6, or 7 days, and then proceed to step (3); (3) detecting estradiol-ER binding activity; wherein (i) if the ER binding activity is not detectable or is below a predetermined threshold level, continue administering the second dosage (i.e., maintain the dosage level); or (ii) if the ER binding activity is detectable or is higher than a predetermined threshold level, administer a third dosage higher than the second dosage (e.g., the second dosage + about 50 to about 200 mg) for 3, 4, 5, 6, or 7 days, and then proceed to step (4); (4) repeating the above steps through a fourth dosage, a fifth dosage, etc. until the ER binding activity is no longer detected comprising.

[0101] In one aspect, the invention includes the use of PET imaging for detecting and / or administering to ER-sensitive or ER-resistant cancers.

[0102] Combinations for the methods disclosed herein Another aspect of the invention relates to a pharmaceutical composition comprising RAD1901 or a solvate (e.g., hydrate) or salt thereof and / or abemaciclib in a therapeutically effective amount for the combination methods described herein.

[0103] The following examples are provided to better illustrate the claimed invention and should not be construed as limiting the scope of the invention. To the extent specific materials are recited, the examples are for illustrative purposes only and are not intended to limit the invention. One of ordinary skill in the art may develop equivalent means or reactants without departing from the inventive capabilities and without departing from the scope of the invention. It is understood that many modifications can be made to the procedures described herein while still remaining within the scope of the invention. It is the intention of the inventors that such modifications be included within the scope of the invention.

Examples

[0104] Example To more fully understand the invention described herein, the following examples are presented. It is to be understood that these examples are for illustrative purposes only and are not to be construed in any way as limiting the invention.

[0105] Example 1: An experimental clinical trial testing the combination of elacestrant (RAD1901) and abemaciclib in women with advanced or metastatic ER+ / HER2- breast cancer Study Objectives: Phase 1 Safety Run-in: To determine the recommended Phase 2 dose (RP2D) of elacestrant in combination with abemaciclib in postmenopausal women with advanced or metastatic ER+ / HER2- breast cancer who have not received prior therapy with a CDK4 / 6 inhibitor or SERD.

[0106] Dose Escalation: To confirm the safety and tolerability of elacestrant in combination with abemaciclib at the selected RP2D in postmenopausal women with advanced or metastatic ER+ / HER2− breast cancer whose disease has progressed on prior endocrine therapy.

[0107] Second To evaluate the clinical benefit rate (CBR) To evaluate the objective response rate (ORR) To evaluate the duration of response (DoR) To evaluate progression-free survival (PFS) To assess the pharmacokinetics (PK) (one or more) of elacestrant in combination with abemaciclib To assess the PK of abemaciclib in combination with elacestrant

[0108] Assays To evaluate genomic changes associated with ER+ breast cancer detected in circulating tumor DNA (ctDNA) and correlate with clinical response. To evaluate biomarkers associated with ER+ breast cancer in fresh and archival tumor biopsies and correlate with clinical response.

[0109] Study Design: This study is designed as a proof-of-concept to evaluate the safety and efficacy of elacestrant in combination with abemaciclib in postmenopausal women with advanced or metastatic ER+ / HER2− breast cancer who have not received prior therapy with a CDK4 / 6 inhibitor or SERD.

[0110] To evaluate the safety and tolerability of elacestrant in combination with abemaciclib, a safety lead-in phase will be conducted to identify the maximum tolerated dose (MTD) and / or RP2D of the combination. After completion of the safety lead-in phase, the dose escalation phase will be opened to enroll 30 new subjects treated at the RP2D provided in Figure 1.

[0111] During the safety lead-in phase, a cohort of 6 subjects is enrolled sequentially at the dose levels provided in Table 1 starting at dose level 1.

Table 1

[0112] The initial cohort evaluates dose level 1 and may investigate lower dose levels based on safety considerations by the study committee and sponsor (Table 1). If necessary, additional patients, intermediate doses, or alternative dosing schedules may be investigated to better define the safety, tolerability, and PK of the elacestrant + abemaciclib combination.

[0113] The MTD is defined as the maximum dose level at which < 33% of subjects experience dose-limiting toxicity (DLT) during the first 28 days of treatment when administered to 0 / 6 or 1 / 6 subjects or additional subjects (Table 2). It is estimated that 2 - 3 dose levels will be required to determine the MTD and / or RP2D. The RP2D is selected by the study committee and sponsor based on safety evaluations, PK, and preliminary efficacy data. In the dose escalation phase of the trial, 30 new subjects are enrolled to further evaluate the tolerability and potency of the drug combination at the selected RP2D.

[0114] Elacestrant is administered orally once daily at 400 or 300 mg in a continuous dosing schedule. Abemaciclib is co-administered orally twice daily at 150 or 100 mg in a daily continuous schedule.

Table 2 - 1

Table 2 - 2

[0115] Dose Adjustment and Administration Delay All efforts are made to administer the investigational drug at the planned dose and schedule. However, as described in Tables 3, 4, 5, and 6, dose adjustments or delays may be possible in the event of significant treatment-related toxicity events. Subjects who require more than two dose reductions of both investigational drugs will have the study discontinued.

[0116] If drug-related toxicity requires discontinuation of treatment with the suspected drug(s), the subject may continue to receive the other drug(s) alone. If the suspected drug-related toxicity has not resolved to the extent that a new cycle of combination therapy can be initiated on the planned day 1 of the next cycle, the other drug(s) may be continued and the suspected drug(s) will be adjusted as described in Tables 3, 4, 5, and 6 until the toxicity resolves. If abemaciclib-related toxicity requires abemaciclib discontinuation, the subject may continue to receive elacestrant alone until either progressive disease (PD), symptomatic worsening, unacceptable toxicity, death, or withdrawal of consent occurs first. If elacestrant-related toxicity requires elacestrant discontinuation, the subject may continue to receive abemaciclib alone until either progressive disease (PD), symptomatic worsening, unacceptable toxicity, death, or withdrawal of consent occurs first. If toxicity related to both drugs has not resolved to the extent that a new cycle of combination therapy can be initiated on the planned day 1 of the next cycle, dosing may be delayed as described in Tables 3, 4, 5, and 6 until the toxicity resolves.

Table 3-1

Table 3-2

Table 4

Table 5

Table 6

[0117] Subject population: Postmenopausal women with advanced, progressive or metastatic ER+ / HER2− breast cancer whose disease has progressed on prior AI therapy.

[0118] Inclusion and exclusion criteria: Subjects must meet all of the following inclusion criteria and have no exclusion criteria:

[0119] Inclusion criteria · Subjects with a histologically or cytologically confirmed diagnosis of breast adenocarcinoma with evidence of recurrent (either local or metastatic) disease. · Subjects must have measurable and / or evaluable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Tumor lesions previously treated with radiotherapy or other locoregional therapy are considered measurable and / or evaluable only if disease progression is clearly demonstrated after completion of locoregional therapy. Bone lesions or mixed lytic-blastic lesions that can be evaluated by cross-sectional imaging techniques such as CT or MRI may be considered evaluable lesions if they meet the definition of evaluable disease as defined by RECIST v1.1. Blastic bone lesions are evaluable lesions. · Subjects must be: a. Recorded as having undergone bilateral surgical oophorectomy b. Aged ≥60 years and amenorrheic for ≥1 year since their last menstrual period c. Aged <60 years, amenorrheic for ≥1 year since their last menstrual period, with no pathological or physiological alternative cause (including treatment with chemotherapy, tamoxifen or toremifene, or GnRH agonists), and with serum estradiol and FSH levels within the laboratory reference range for postmenopausal women and defined as postmenopausal women. · Aged ≥18 years · The subject must have the following tumor status as confirmed by local laboratory testing on a recent biopsy of the subject from a primary tumor or metastatic lesion: a. ER+ tumors with IHC staining of ≧1% as defined in the 2010 American Society of Clinical Oncology (ASCO) recommendations for ER testing b. HER2- tumors with IHC results of 0 or 1+ for cell membrane protein expression or in situ hybridization (ISH) negative results as defined in the 2013 ASCO recommendations for HER2 testing · must not have · The subject may have received up to 2 prior lines of endocrine therapy without CDK4 / 6 inhibitors or SERD for advanced or metastatic disease, and must have no documented evidence of new metastatic disease or progression of previously treated metastatic disease. · The subject may have received 1 prior chemotherapy regimen in the advanced / metastatic setting (prior adjuvant chemotherapy is permitted if ≧12 months before registration). Chemotherapy administered for less than 1 cycle is not counted as a prior line of therapy. · Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. · Resolution of all toxic effects of prior therapy or surgical procedures to grade ≦1 (excluding alopecia and peripheral neuropathy). · The following: a. Hematologic function i. Absolute neutrophil count (ANC) ≧1500 / μL ii. Platelet count ≧100,000 / μL iii. Hemoglobin ≧8.0 gm / dL. The patient may receive red blood cell transfusions at the discretion of the investigator to achieve this hemoglobin level; the first study drug treatment must not start earlier than the day after the red blood cell transfusion. b. Renal function i. Serum creatinine calculated by the Cockcroft-Gault formula ≥ 30 mL / min c. Liver function i. Alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN) ii. Aspartate aminotransferase (AST) ≤ 3 x ULN iii. Total bilirubin ≤ ULN, or direct bilirubin ≤ ULN in subjects with Dubin-Johnson syndrome when total bilirubin ≤ 1.5 x ULN. d. Chemistry i. Potassium, sodium, calcium (corrected for albumin), magnesium, and phosphorus are within the laboratory normal range. If the screening evaluation is abnormal, the chemistry evaluation may be repeated up to 2 times; the subject may receive appropriate supplementation prior to re-evaluation e. Coagulation i. INR ≤ 1.5 Adequate organ function as defined Note: Subjects on anticoagulant therapy may be related to a stable INR within the therapeutic range for at least 1 month prior to the first administration of the investigational drug in the absence of any exclusionary medical conditions, provided that AI is the appropriate therapy for the subject. · Ability to read, understand, and sign the informed consent document

[0120] Exclusion Criteria · Prior treatment with fulvestrant or a CDK4 / 6 inhibitor · Prior treatment with elacestrant (RAD1901), GDC-0810, GDC-0927, GDC-9545, LSZ102, AZD9496, bazedoxifene, or other investigational SERD or ER antagonists · The following windows a. Any endocrine therapy within 14 days prior to the first administration of the investigational treatment b. Any chemotherapy within 21 days prior to the first administration of the investigational treatment c. Any investigational anticancer drug therapy within 21 days prior to the first administration of the investigational treatment or 3 half-lives (whichever is longer) Previous anticancer or investigational drug treatment within · Presence of symptomatic metastatic visceral disease defined as extensive liver involvement, untreated or progressive CNS metastases, or symptomatic pulmonary lymphangitic spread. Subjects with separate pulmonary parenchymal metastases are eligible, provided that the subject's respiratory function is not significantly compromised as a result of the disease in the investigator's opinion. Subjects previously treated for CNS metastases are eligible, provided that all known lesions have been previously treated, the lesions had completed radiotherapy at least 28 days prior to the first administration of the investigational drug, are clinically stable, and do not require steroid medications. If an anticonvulsant medication is required, the subject must be stable against the non-enzymes that induce the anticonvulsant regimen. · Subjects with a uterus who have a history of endometrial intraepithelial carcinoma (indeterminate endometrial hyperplasia or higher-grade lesions). · Diagnosis of any other malignancy within 3 years prior to enrollment, excluding appropriately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix. · Within 6 months prior to enrollment, any of the following: myocardial infarction, severe / unstable angina, ongoing arrhythmia of grade ≥ 2, prolonged QTcF of grade ≥ 2, uncontrolled atrial fibrillation of any grade, coronary / peripheral arterial bypass graft, heart failure of class ≥ II as defined by the New York Heart Association (NYHA) guidelines, or a cerebrovascular disorder including transient ischemic attack or symptomatic pulmonary embolism. · Subjects with a history of abnormal coagulation profile or coagulation disorder within the past 6 months, including a history of deep vein thrombosis (DVT) or pulmonary embolism. The following conditions: a. Subjects with appropriately treated catheter-related venous thrombosis that occurred more than 1 month prior to the first administration of the investigational drug. b. Subjects who have experienced a decisive event more than 6 months before enrollment, or who have been treated with an anticoagulant, such as warfarin or heparin, for other stable and acceptable medical conditions (e.g., well-controlled atrial fibrillation), and for whom the provided dose and coagulation parameters (defined by local medical standards) have been stable for at least 1 month prior to the first administration of the test treatment. Subjects with · Subjects who have known difficulties with oral medications, or who have any of the following diagnoses: severe diarrhea, uncontrolled nausea or vomiting, gastrointestinal (GI) obstructive motility disorders, malabsorption syndrome, or gastric bypass. · Subjects who are receiving medical treatment or who are consuming herbal supplements and / or fruits (e.g., pomelo, grapefruit, sour orange) known to be strong inhibitors or inducers of CYP3A4 that cannot be discontinued within the longer of the first 5 half-lives or 14 days prior to study entry and during the duration of the study. · Major surgery within 28 days prior to the first administration of the test treatment. · Radiation therapy within 14 days prior to the first administration of the test treatment. The irradiated lesion should not be selected as the target lesion. · Any concurrent severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or administration of the investigational product or interfere with the interpretation of study results and, in the investigator's judgment, makes the individual inappropriate for entry into this study.

[0121] Duration of therapy: Subjects continue to receive treatment until the first occurrence of confirmed PD, unacceptable toxicity, death, or withdrawal of consent.

[0122] Duration of follow-up: All subjects are followed up until 30 days after treatment or until all treatment-related AEs have resolved or stabilized to grade 2 or less.

[0123] Duration of study conduct: For approximately 36 months or until the last subject completes the test treatment and a 30-day follow-up period.

[0124] Investigational product, dose, and mode of administration: Elacestrant is supplied as 100 or 400 mg tablets and is administered orally daily on a continuous dosing schedule. The starting dose for the safety lead-in phase is 400 mg.

[0125] Abemaciclib is supplied as 100 or 150 mg tablets and is administered twice daily on a continuous daily dosing schedule. The starting dose for the safety lead-in phase is 150 mg.

[0126] Study endpoints: First Safety lead-in: Frequency of DLT during the first 28 days of treatment with elacestrant in combination with abemaciclib treatment.

[0127] Dose escalation: Incidence of all adverse events (AEs), all serious adverse events (SAEs), review of laboratory data (including hematology and chemistry), ECG monitoring, physical examination, performance status, and vital signs.

[0128] Second CBR is defined as the proportion of subjects with the best overall response of complete response (CR), partial response (PR), or stable disease (SD) for ≥ 24 weeks. Tumor response is determined by the investigator according to the RECIST v1.1 guidelines.

[0129] ORR is defined as the proportion of subjects with the best overall response of CR or PR. Tumor response is determined by the investigator according to RECIST v1.1.

[0130] DoR is calculated as the time from the date of the first recorded response (CR or PR) to the date of the first recorded tumor progression. Tumor response and progression are determined by the investigator according to RECIST v1.1.

[0131] PFS is calculated as the length of time from the first dose until the earlier of the date of disease progression recorded by RECIST v1.1 or death from any cause.

[0132] Pharmacokinetic parameters include area under the concentration-time curve (AUC), time to maximum concentration (tmax), maximum plasma concentration (Cmax), oral clearance (CL / F) and other PK parameters as appropriate.

[0133] Examination Serial blood samples are analyzed for genomic changes related to ER+ breast cancer in circulating tumor DNA (ctDNA). Tumor biopsies are analyzed for biomarkers related to ER+ breast cancer.

[0134] Number of subjects: Up to 48 subjects are enrolled and up to 36 subjects are treated at the RP2D. This allows for up to 3 dose levels to be taken in the safety lead-in phase, with cohorts of 6 subjects each (6 - 18 subjects) and an additional 30 subjects enrolled during the dose expansion phase. Subjects who discontinue treatment before completing the safety lead-in phase (days 1 - 28) for reasons other than toxicity may be replaced.

[0135] Sample size assumption: The sample size in the safety lead-in phase is typical for a dose escalation study. The safety lead-in phase evaluates up to 3 dose levels in cohorts of 6 subjects each; the total sample size is expected to be 6 - 18 subjects depending on the number of cohorts.

[0136] Approximately 30 new subjects are enrolled in the dose expansion phase. A total of approximately 36 subjects are treated at the RP2D (30 from the dose expansion phase + approximately 6 subjects from the safety lead-in phase), and the study has a greater than 90% chance of detecting AEs at an incidence rate of 7% or greater.

[0137] Although not the primary objective, the dose escalation phase is used to generate preliminary efficacy data for combination therapy. Assuming a 75% CBR at 24 weeks, a total of 32 evaluable subjects (36 subjects - 10% dropout) would have a 95% lower confidence limit of 58% based on the Wilson method.

[0138] The primary data analysis occurs approximately 18 months after the last subject is enrolled. Subjects are followed for objective disease progression until approximately 50% of the subjects have died or experienced objective disease progression, at which point a final analysis is conducted.

[0139] Example 2: An experimental clinical trial testing the combination of elacestrant and abemaciclib for the treatment of ER+ / HER2- advanced breast cancer (comparing to investigator's choice of non-steroidal aromatase inhibitor + abemaciclib or fulvestrant + abemaciclib) Study Overview This is an international, multi-center, randomized, active-control, open-label, phase 3 clinical trial comparing the efficacy and safety of elacestrant combined with abemaciclib vs. letrozole or fulvestrant combined with abemaciclib in subjects with ER+ / HER2- advanced / metastatic breast cancer who have not received prior treatment with a CDK4 / 6 inhibitor or SERD and who progressed during or after prior adjuvant or metastatic endocrine therapy. The primary objective is to show that the combination of elacestrant + abemaciclib is superior to 1) the combination of letrozole and abemaciclib or 2) the combination of anastrozole and abemaciclib or 3) the combination of fulvestrant and abemaciclib in terms of prolonging PFS.

[0140] Approximately 600 (HR < 0.7) or 1000 (HR < 0.8) subjects will be: a. elacestrant + abemaciclib b. investigator's choice of non-steroidal aromatase inhibitor (AI) (letrozole / anastrozole) + abemaciclib or fulvestrant + abemaciclib Randomize 1:1 to receive either of the following.

[0141] Elacestrant: Dose TBD (up to 400 mg), continuous dosing schedule, once daily orally. Abemaciclib: 125 mg, twice daily on a continuous dosing schedule. Letrozole: 2.5 mg, continuous dosing schedule, once daily orally. Anastrozole: 1 mg, once daily orally. Fulvestrant: 500 mg per label.

[0142] Endpoints: First endpoint a. Progression-free survival (PFS)

[0143] Second endpoint a. Overall survival (OS) b. Objective response rate (ORR) c. Duration of response (DoR) d. Clinical benefit rate (CBR) e. Safety and tolerability f. Pharmacokinetics (PK) g. Quality of life (QoL)

[0144] Example 3: An experimental clinical trial testing the combination of elacestrant and abemaciclib for first-line treatment of ER+ / HER2− advanced breast cancer Trial overview This is an international, multicenter, randomized, active-control, open-label, phase 3 clinical trial comparing the efficacy and safety of elacestrant in combination with abemaciclib vs letrozole in combination with abemaciclib in subjects with ER+ / HER2− advanced / metastatic breast cancer who have not received prior systemic anti-cancer therapy for their advanced / metastatic disease and have not received prior treatment with a CDK4 / 6 inhibitor or SERD. The primary objective is to show that the combination of elacestrant + abemaciclib is superior to letrozole + abemaciclib in terms of prolongation of PFS.

[0145] Approximately 650 (HR<0.7) or 1100 (HR<0.8) subjects: a. Elacestrant + Abemaciclib b. Letrozole + Abemaciclib Patients will be randomized 1:1 to receive either

[0146] Elacestrant: Dose TBD (up to 400 mg), continuous dosing schedule, orally once daily. Abemaciclib: 125 mg twice daily on a continuous dosing schedule. Letrozole: 2.5 mg, continuous schedule, orally once daily.

[0147] the last stop: First End Point Progression-free survival (PFS)

[0148] Second End Point a. Overall survival OS b. Objective response rate (ORR) c. Duration of Response (DoR) d. Clinical Benefit Rate (CBR) e. Safety and Tolerability f. Pharmacokinetics (PK) g. Quality of Life (QoL)

[0149] Example 4: Experimental clinical trial testing the combination of elacestrant and abemaciclib versus abemaciclib alone for the treatment of ER+ / HER2- advanced breast cancer Test Overview This is an international, multi-center, randomized, active-control, double-blind, phase 3 clinical trial comparing the efficacy and safety of elacestrant in combination with abemaciclib versus abemaciclib alone in subjects with ER+ / HER2- advanced / metastatic breast cancer who have received ≤2 prior chemotherapy regimens for advanced / metastatic disease of the subject and have received prior systemic anti-cancer therapy that does not include a CDK4 / 6 inhibitor or SERD. The primary objective is to show that the combination of elacestrant + abemaciclib is superior to abemaciclib alone in terms of prolonging PFS.

[0150] Approximately 500 subjects (HR<0.7) will be: a. randomized 2:1 to receive either b. elacestrant + abemaciclib c. abemaciclib.

[0151] Elacestrant: dose TBD (up to 400 mg), continuous dosing schedule, orally once daily. Abemaciclib: 150 mg twice daily on a continuous daily schedule in combination, or 200 mg twice daily orally as monotherapy.

[0152] Endpoints: First endpoint a. Progression-free survival (PFS)

[0153] Second endpoint a. Overall survival (OS) b. Objective response rate (ORR) c. Duration of response (DoR) d. Clinical benefit rate (CBR) e. Safety and tolerability f. Pharmacokinetics (PK) g. Quality of life (QoL)

[0154] Other aspects All publications and patents cited in this disclosure are hereby incorporated by reference into this specification to the same extent as if each individual publication and patent application were specifically and individually indicated to be incorporated by reference. In case of any conflict between the meaning of terms in any incorporated patent or publication and the meaning of terms used in this disclosure, the meaning of terms in this disclosure is intended to be controlling. Further, the foregoing discussion is merely illustrative of exemplary aspects of the invention. Those skilled in the art will readily appreciate from such discussion, as well as from the accompanying drawings and claims, that various changes, modifications, and variations can be made to the invention without departing from the spirit and scope of the invention as defined in the following claims.

[0155] Aspects of the invention include the following. Item 1 A method of treating breast cancer in a patient, comprising the step of administering to the patient a therapeutic combination comprising elacestrant or a pharmaceutically acceptable salt thereof and abemaciclib or a pharmaceutically acceptable salt thereof. Item 2 The method according to item 1, wherein the patient is a postmenopausal woman. Item 3 The method according to item 1, wherein the patient has not received previous treatment with a CDK4 / 6 inhibitor or SERD. Item 4 The method according to item 1, wherein the breast cancer in the patient has progressed from previous endocrine therapy. Item 5 The method according to item 1, wherein the breast cancer in the patient is ER+ breast cancer. Item 6 The method according to item 5, wherein the breast cancer in the patient is HER2- breast cancer. Item 7 The method according to item 1, wherein the breast cancer in the patient is advanced or metastatic breast cancer. Item 8 The method according to item 1, wherein elacestrant is administered to the patient at a dose of 200 to 500 mg / day. Item 9 The method according to item 8, wherein elacestrant is administered to a patient at a dose of 250 to 450 mg / day. Item 10 The method according to item 9, wherein elacestrant is administered to a patient at a dose of about 300 mg / day. Item 11 The method according to item 10, wherein elacestrant is administered to a patient at a dose of about 300 mg / day in a once-daily administration. Item 12 The method according to item 9, wherein elacestrant is administered to a patient at a dose of about 400 mg / day. Item 13 The method according to item 12, wherein elacestrant is administered to a patient at a dose of about 400 mg / day in a once-daily administration. Item 14 The method according to item 1, wherein abemaciclib is administered to a patient at a dose of 150 to 400 mg / day. Item 15 The method according to item 14, wherein abemaciclib is administered to a patient at a dose of about 200 mg / day. Item 16 The method according to item 15, wherein abemaciclib is administered to a patient at a dose of about 200 mg / day in a twice-daily administration. Item 17 The method according to item 16, wherein abemaciclib is administered to a patient at a dose of about 100 mg twice daily. Item 18 The method according to item 14, wherein abemaciclib is administered to a patient at a dose of about 300 mg / day. Item 19 The method according to item 18, wherein abemaciclib is administered to a patient at a dose of about 300 mg / day in a twice-daily administration. Item 20 The method according to item 19, wherein abemaciclib is administered to a patient at a dose of about 150 mg twice daily. Item 21 The method according to item 1, wherein elacestrant is administered to a patient at a dose of about 400 mg / day and abemaciclib is administered to a patient at a dose of about 300 mg / day. Item 22 The method according to paragraph 21, wherein abemaciclib is administered to a patient at a dose of 150 mg twice a day. Paragraph 23 The method according to paragraph 1, wherein elacestrant is administered to a patient at a dose of about 300 mg / day and abemaciclib is administered to a patient at a dose of about 300 mg / day. Paragraph 24 The method according to paragraph 23, wherein abemaciclib is administered to a patient at a dose of 150 mg twice a day. Paragraph 25 The method according to paragraph 1, wherein elacestrant is administered to a patient at a dose of about 300 mg / day and abemaciclib is administered to a patient at a dose of about 200 mg / day. Paragraph 26 The method according to paragraph 25, wherein abemaciclib is administered to a patient at a dose of 100 mg twice a day. Paragraph 27 The method according to paragraph 1, wherein elacestrant is administered to a patient at the maximum tolerated dose for the patient. Paragraph 28 The method according to paragraph 1, wherein abemaciclib is administered to a patient at the maximum tolerated dose for the patient. Paragraph 29 The method according to paragraph 1, wherein a patient experiences a longer progression-free survival time compared to a patient administered a combination of letrozole and abemaciclib, a combination of anastrozole and abemaciclib, or a combination of fulvestrant and abemaciclib. Paragraph 30 The method according to paragraph 29, wherein the breast cancer is ER+ / HER2− advanced or metastatic breast cancer, the patient has progressed during or after previous adjuvant or metastatic endocrine therapy, and has not received previous treatment with a CDK4 / 6 inhibitor or SERD. Paragraph 31 The method according to paragraph 29, wherein a patient administered a combination of letrozole and abemaciclib is administered 2.5 mg of letrozole once a day and 125 mg of abemaciclib twice a day. Paragraph 32 The method according to paragraph 29, wherein the patient is administered a combination of anastrozole and abemaciclib, at a dose of 1 mg of anastrozole once daily and 125 mg of abemaciclib twice daily. Paragraph 33 The method according to paragraph 29, wherein the patient is administered a combination of fulvestrant and abemaciclib, as two 5 mL intramuscular injections into the buttocks (buttock region) at a rate of 1 to 2 minutes per injection, once in each buttock, on days 1, 15 and 29 and then monthly, of 500 mg of fulvestrant injection and 125 mg of abemaciclib twice daily. Paragraph 34 The method according to paragraph 29, wherein the patient experiences a greater progression-free survival time compared to a patient administered a combination of letrozole and abemaciclib, the breast cancer is ER+ / HER2− advanced or metastatic breast cancer, the patient has not received prior systemic anti-cancer therapy for the patient's advanced / metastatic disease, and has not received prior treatment with a CDK4 / 6 inhibitor or SERD. Paragraph 35 The method according to paragraph 34, wherein the patient is administered a combination of letrozole and abemaciclib, at a dose of 2.5 mg of letrozole once daily and 125 mg of abemaciclib twice daily. Paragraph 36 The method according to paragraph 1, wherein the patient experiences a greater progression-free survival time compared to a patient administered abemaciclib as monotherapy. Paragraph 37 The method according to paragraph 36, wherein the breast cancer is ER+ / HER2− advanced or metastatic breast cancer, the patient has received prior systemic anti-cancer therapy for the patient's advanced or metastatic disease, including ≤2 prior chemotherapy for metastatic breast cancer permitted for the patient, and the prior systemic anti-cancer therapy did not include a CDK4 / 6 inhibitor or SERD. Paragraph 38 The method according to paragraph 36, wherein the patient administered abemaciclib as monotherapy is administered 200 mg of abemaciclib twice daily.

Claims

[Claim 1] A method of treating breast cancer in a patient, comprising administering to the patient a therapeutic combination comprising elacestrant, or a pharma- ceutically acceptable salt thereof, and abemaciclib, or a pharma- ceutically acceptable salt thereof.

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