RU2847580C1 - Therapeutic agent for breast cancer - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: disclosed are the use and method of treating breast cancer, in which resistance to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has developed and oestrogen receptor antagonists, which comprises administering 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide of formula (I), or a pharmacologically acceptable salt thereof in dose of 25 mg to 500 mg per day to a patient in need thereof, without combination with CDK4/6 inhibitors and oestrogen receptor antagonists.

EFFECT: invention provides the therapeutic agent for treating breast cancer accompanied by developing resistance to the CDK4/6 inhibitors and oestrogen receptor antagonists.

22 cl, 2 dwg, 2 tbl, 1 ex

Description

Field of technology to which the invention relates

[0001] The present invention relates to a therapeutic agent for breast cancer, which comprises a monocyclic pyridine derivative or a pharmacologically acceptable salt thereof having an inhibitory activity against FGFR. More particularly, the present invention relates to a therapeutic agent for breast cancer, which comprises 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide or a pharmacologically acceptable salt thereof.

State of the art

[0002] [Chemical formula 1]

[0003] The compound 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide represented by the formula (I) is known as an inhibitor of fibroblast growth factor receptors (FGFR) 1, 2 and 3 and has been reported to have a cell growth inhibitory effect on gastric cancer, lung cancer, bladder cancer and endometrial cancer (PTL 1). The compound has also been reported to have a strong therapeutic effect on bile duct cancer (PTL 2), breast cancer (PTL 3) and hepatocellular carcinoma (PTL 4). Known pharmacologically acceptable salts of the compound include succinic acid salts and maleic acid salts (PTL 5).

[0004] Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors such as palbociclib and abemaciclib are used to treat estrogen receptor-positive, HER2-negative (NPL 1) breast cancer.

Estrogen receptor antagonists such as tamoxifen and fulvestrant are also used to treat estrogen receptor-positive (NPL 2) breast cancer.

[0005] Breast cancer is classified based on the expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), and drug therapy is administered to match each type, along with surgery to remove the affected area.

[0006] Estrogen receptor-positive and HER2-positive breast cancer types represent a significant proportion of patients with breast cancer. Administration of palbociclib and fulvestrant to patients with these breast cancer types has been reported to significantly improve the overall response rate (ORR) compared with administration of fulvestrant alone (NPL 3). However, continuous administration of palbociclib and fulvestrant has also been reported to induce resistance, leading to loss of effect (NPL 4).

List of references

Patent literature sources

[0007] [PTL 1] U.S. Patent Application Publication No. 2014-0235614

[PTL 2] U.S. Patent Application Publication No. 2018-0015079

[PTL 3] U.S. Patent Application Publication No. 2018-0303817

[PTL 4] International Patent Application Publication No. WO 2019/189241

[PTL 5] U.S. Patent Application Publication No. 2017-0217935

Non-patent literature sources

[0008] [NPL 1] Bottcher et al., Acta Oncologica, 2019, 58(2), 147-153.

[NPL 2] Howell et al., Journal of Clinical Oncology, 2004, 22(9), 1605-1613.

[NPL 3] Seki et al., In Vivo, 2019, 33, 2037-2044.

[NPL 4] Nayar et al., Nature Genetics, 2019, 51, 207-216.

The essence of the invention

Technical challenge

[0009] The object of the present invention is to provide a therapeutic agent for breast cancer that has developed resistance to the administration of CDK4/6 inhibitors and estrogen receptor antagonists.

Solution to the problem

[0010] As a result of conducting a large number of studies in light of the current situation, the present inventors completed the present invention upon discovering that the compound represented by the formula (I) above exhibits a strong therapeutic effect on breast cancer that has developed resistance to the administration of CDK4/6 inhibitors and estrogen antagonists.

[0011] In particular, the present invention provides the following [1] - [24].

[1] A therapeutic agent for the treatment of breast cancer that has developed resistance to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and estrogen receptor antagonists, wherein the therapeutic agent comprises 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide represented by formula (I), or a pharmacologically acceptable salt thereof.

[Chemical formula 2]

[2] A therapeutic agent for the treatment of breast cancer, comprising a CDK4/6 inhibitor and an estrogen receptor antagonist, which is administered in combination with 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide represented by formula (I), or a pharmacologically acceptable salt thereof.

[Chemical formula 3]

[3] A therapeutic agent for the treatment of breast cancer, containing 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide represented by formula (I), or a pharmacologically acceptable salt thereof, which is administered in combination with a CDK4/6 inhibitor and an estrogen receptor antagonist.

[Chemical formula 4]

[4] The therapeutic agent according to [2] or [3] above, wherein 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide represented by formula (I) or a pharmacologically acceptable salt thereof is administered after administration of a CDK4/6 inhibitor and an estrogen receptor antagonist.

[Chemical formula 5]

[0012] [5] A composition for the treatment of breast cancer that has developed resistance to CDK4/6 inhibitors and estrogen receptor antagonists, wherein the composition comprises 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide represented by formula (I), or a pharmacologically acceptable salt thereof.

[6] A composition for the treatment of breast cancer comprising a CDK4/6 inhibitor and an estrogen receptor antagonist, which is administered in combination with 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide represented by formula (I), or a pharmacologically acceptable salt thereof.

[7] A composition for treating breast cancer, containing 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide represented by formula (I), or a pharmacologically acceptable salt thereof, which is administered in combination with a CDK4/6 inhibitor and an estrogen receptor antagonist.

[8] The composition according to [6] or [7] above, wherein 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide represented by formula (I) or a pharmacologically acceptable salt thereof is administered after administration of a CDK4/6 inhibitor and an estrogen receptor antagonist.

[0013] [9] A method for treating breast cancer that has developed resistance to CDK4/6 inhibitors and estrogen receptor antagonists, the method comprising administering 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide represented by formula (I) or a pharmacologically acceptable salt thereof to a patient in need thereof.

[10] A method for treating breast cancer, which comprises administering 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide represented by formula (I), or a pharmacologically acceptable salt thereof, a CDK4/6 inhibitor and an estrogen receptor antagonist to a patient in need thereof.

[11] The method according to [10] above, which comprises administering 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide represented by formula (I), or a pharmacologically acceptable salt thereof, to a patient in need thereof, after administration of a CDK4/6 inhibitor and an estrogen receptor antagonist.

[0014] [12] A compound which is 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide represented by formula (I) or a pharmacologically acceptable salt thereof for use in the treatment of breast cancer which has developed resistance to CDK4/6 inhibitors and estrogen receptor antagonists.

[13] Use of 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide represented by formula (I) or a pharmacologically acceptable salt thereof for the preparation of a therapeutic agent for the treatment of breast cancer that has developed resistance to CDK4/6 inhibitors and estrogen receptor antagonists.

[0015] [14] The above-mentioned therapeutic agent, composition, method of treatment, compound or use, wherein the pharmacologically acceptable salt is 1,5-succinate.

[15] The above-mentioned therapeutic agent, composition, method of treatment, compound or use, wherein the breast cancer is breast cancer that has developed resistance to CDK4/6 inhibitors and estrogen receptor antagonists.

[16] The above-mentioned therapeutic agent, composition, method of treatment, compound, or use, wherein the breast cancer is estrogen receptor positive.

[17] The above-mentioned therapeutic agent, composition, method of treatment, compound or use, wherein the breast cancer is human epidermal growth factor receptor type 2 (HER2) positive.

[18] The above-mentioned therapeutic agent, composition, method of treatment, compound or use, wherein the CDK4/6 inhibitor is one or more selected from the group consisting of palbociclib, abemaciclib and ribociclib.

[19] The above-mentioned therapeutic agent, composition, method of treatment, compound, or use, wherein the CDK4/6 inhibitor is palbociclib.

[20] The above-mentioned therapeutic agent, composition, method of treatment, compound or use, wherein the estrogen receptor antagonist is one or more selected from the group consisting of tamoxifen, fulvestrant and mepitiostane.

[21] The above-mentioned therapeutic agent, composition, method of treatment, compound or use, wherein the estrogen receptor antagonist is fulvestrant.

[22] The above-mentioned therapeutic agent, composition, method of treatment, compound or use, wherein the breast cancer is locally advanced breast cancer, metastatic breast cancer, recurrent breast cancer or unresectable breast cancer.

[23] The above-mentioned therapeutic agent, composition, method of treatment, compound or use, wherein the breast cancer expresses fibroblast growth factor receptor (FGFR).

[24] The above-mentioned therapeutic agent, composition, method of treatment, compound or use, wherein the FGFR is FGFR1, FGFR2 or FGFR3.

Beneficial effects of the invention

[0016] The compound represented by formula (I) can potentially exhibit a tumor volume-reducing effect in breast cancer that has developed resistance to the administration of CDK4/6 inhibitors and estrogen antagonists.

Brief description of graphic materials

[0017] Fig. 1 is a graph showing the transition in mean tumor volume in different groups after initiation of drug administration.

Fig. 2 is a graph showing the transition of average tumor volume in different groups after the start of drug administration.

Description of embodiments

[0018] The compound represented by formula (I) and pharmacologically acceptable salts thereof according to the present invention can be produced by the method described in PTL 1.

[0019] As used herein, "pharmacologically acceptable salt" means, for example, a salt of an inorganic acid, a salt of an organic acid, or a salt of an acidic amino acid.

[0020] Preferred examples of inorganic acid salts include salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid.

[0021] Preferred examples of salts with organic acids include salts with acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, and p -toluenesulfonic acid.

[0022] Preferred examples of acidic amino acid salts include aspartic acid and glutamic acid salts.

[0023] Preferred pharmacologically acceptable salts are succinic acid salts or maleic acid salts, with succinic acid salts being more preferred. Particularly preferred are 1,5-succinic acid salts (hereinafter, the 1,5-succinic acid salt of the compound represented by formula (I) will be shown as compound A).

[0024] The therapeutic agent for breast cancer of the present invention can be administered orally in the form of a solid composition such as a tablet, granules, fine granules, powder or capsule, or a liquid preparation, jelly or syrup. The therapeutic agent for breast cancer of the present invention can also be administered parenterally in the form of an injection, suppository, ointment or poultice.

[0025] The therapeutic agent for breast cancer of the present invention can be formulated by the method described in the Japanese Pharmacopoeia, 17th Edition.

[0026] The dose of the compound represented by formula (I) or a pharmacologically acceptable salt thereof can be appropriately selected depending on the severity of the symptoms, age, sex, body weight and sensitivity of the patient, the route of administration, the period of administration, the interval of administration and the type of medicinal formulation. Generally, it will be 0.5 mg to 5 g, preferably 1 mg to 1 g, and more preferably 1 mg to 500 mg per day, for oral administration to adults (body weight 60 kg). It can be administered in 1 to 3 doses per day.

[0027] As used herein, a "cyclin-dependent kinase 4/6 (CDK4/6) inhibitor" is a drug that inhibits the activity of CDK4 and CDK6, which are enzymes activated in cancer cells and promote unregulated cell division.

[0028] Preferred examples of CDK4/6 inhibitors include palbociclib, abemaciclib, and ribociclib. Palbociclib is the most preferred among them.

[0029] The dosage and route of administration of a CDK4/6 inhibitor using palbociclib for an average adult, for example, may be oral administration of 125 mg once daily for a continuous period of 3 weeks, followed by a pause period of one week. This administration cycle may then be repeated.

[0030] If the CDK4/6 inhibitor is ribociclib, used in the average adult, it can be administered orally at 600 mg once daily for a continuous period of 3 weeks, followed by a one-week rest period. This dosing cycle can then be repeated.

[0031] If the CDK4/6 inhibitor is abemaciclib and is used in the average adult, it may be administered orally at 150 mg per dose administered twice daily.

[0032] As used herein, an "estrogen receptor antagonist" is a drug that binds to estrogen receptors expressed on breast cancer cells. This mechanism can be used to inhibit the binding between estrogen receptors and estrogen, thereby reducing the proliferation of breast cancer cells.

[0033] Preferred examples of estrogen receptor antagonists include tamoxifen, fulvestrant and mepitiostane, with fulvestrant being the most preferred.

[0034] The dosage and route of administration of the estrogen receptor antagonist, using fulvestrant as an example, may be intramuscular administration of 500 mg for each dose, initially, after 2 weeks and after 4 weeks and then every 4 weeks.

[0035] If the estrogen receptor antagonist is tamoxifen, it can be administered orally at a dose of 20-40 mg per day.

[0036] If the estrogen receptor antagonist is mepitiostane, it can be administered orally at a dose of 20 mg per day, divided into two doses.

[0037] An aromatase inhibitor, which inhibits estrogen synthesis, can also be used instead of an estrogen receptor antagonist. Preferred examples of aromatase inhibitors include anastrozole, letrozole, and exemestane.

[0038] As used herein, "breast cancer" means a benign or malignant tumor that develops in the mammary glands (ducts or lobules of the mammary gland). This definition includes locally advanced breast cancer, metastatic breast cancer, recurrent breast cancer, and unresectable breast cancer.

[0039] The term "resistance" as used herein means a decrease or loss of effect of a drug during treatment of a breast cancer patient with a CDK4/6 inhibitor and an estrogen receptor antagonist.

[0040] When used herein, the expression "the compound represented by formula (I) or a pharmacologically acceptable salt thereof is administered after administration of a CDK4/6 inhibitor and an estrogen receptor antagonist" means that the compound represented by formula (I) or a pharmacologically acceptable salt thereof is administered separately after development of resistance to administration of the CDK4/6 inhibitor and the estrogen receptor antagonist.

Examples

[0041] The present invention will now be explained in more detail by means of the following examples.

[0042] Example 1. Growth inhibitory effect of compound A after administration of palbociclib and fulvestrant on a tumor obtained from a patient with human breast cancer (OD-BRE-0438)

Using NOD-SCID mice (NOD.CB17-Prkdcscid/J, female, Charles River Japan), with 5-6 mice per group, the antitumor effect of compound A administration after completion of the administration period with palbociclib and fulvestrant was evaluated.

[0043] OD-BRE-0438 is a tumor line from a patient with estrogen receptor-positive breast cancer obtained from Oncodesign Co. Tumor sections were subcutaneously implanted into mice and inoculated. Tumors excised from mice were cut into approximately 4 mm squares, and a trocar (φ 3.5 mm) was used to implant subcutaneously on the right flank of each mouse.

[0044] A 1 mg/ml solution of β-estradiol (FujiFilm-Wako) with 99.5% ethanol (FujiFilm-Wako) was prepared. It was then adjusted to a final concentration of 2.5 μg/ml using ready-to-use sterilized water. Mice were given free access to food from the day of tumor inoculation until the end of the test.

[0045] The long and short axis diameters of the tumors were measured using an electronic digital caliper (Digimatic ^TM caliper, Mitsutoyo Corp.). Tumor volumes were calculated according to the following formula.

Tumor volume (mm ³ ) = long axis diameter (mm) x short axis diameter (mm) x short axis diameter (mm) / 2

[0046] Commercially available palbociclib isethionate (Selleck Chemicals) was adjusted to a concentration of 10 mg/mL with 50 mM sodium lactate buffer (pH 4.0). A commercially available formulation of fulvestrant (trade name: Faslodex 250 mg Intramuscular Injection, AstraZeneca) was used directly.

[0047] Administration of palbociclib and fulvestrant began on day 26 after tumor inoculation. Palbociclib was administered orally once daily for 14 days at a dose of 100 mg/kg (10 mL/kg). Fulvestrant was injected subcutaneously on days 26 and 33 at a dose of 250 mg/kg (5 mL/kg).

[0048] On day 40, the mice were divided into groups such that the mean tumor volumes were approximately the same in each group. The control group consisted of 6 mice, and the compound A group consisted of 5 mice, at different dosages.

[0049] Compound A was dissolved in purified water to a concentration of 2.5 mg/mL.

Compound A was orally administered to mice in each group at a dose of 25 mg/kg (10 ml/kg) or 50 mg/kg (20 ml/kg), once daily for 14 days. The control group was not treated.

[0050] The tumor volume and body weight of each mouse were measured on days 3, 7, 10, and 14 after the start of Compound A administration. The changes in mean tumor volume in each group are shown in Table 1 and Fig. 1.

[0051] [Table 1]

Changes in mean tumor volume after initiation of compound A administration

Day 0 Day 3 Day 7 Day 10 Day 14 Control group (mm ³ ) 278.1 323.1 380.2 408.9 429.6 Compound A, group 25 mg/kg (mm ³ ) 261.4 211.9 167.6 138.3 134.1 Compound A, group 50 mg/kg (mm ³ ) 262.6 174.8 136.1 110.4 96.6

[0052] Reference Example 1. Growth Inhibitory Effect of Compound A on Tumor Derived from Human Breast Cancer Patient (OD-BRE-0438)

The antitumor effect of compound A administration was evaluated using NOD-SCID mice (NOD.CB17-Prkdcscid/J, female, Charles River Japan), with 6 mice per group.

[0053] Tumor sections were implanted subcutaneously in mice and inoculated. Tumors removed from mice were cut into approximately 4 mm squares, and a trocar (φ 3.5 mm) was used to implant subcutaneously on the right side of each mouse to evaluate the antitumor effect.

[0054] A 1 mg/ml solution of β-estradiol (FujiFilm-Wako) with 99.5% ethanol (FujiFilm-Wako) was prepared. It was then adjusted to a final concentration of 2.5 μg/ml using ready-to-use sterilized water. Mice were given free access to food from the day of tumor inoculation until the end of the test.

[0055] Compound A was dissolved in purified water to a concentration of 2.5 mg/mL.

On day 32 post-tumor inoculation, mice were divided into groups such that mean tumor volumes were approximately equal in each group. Tumor volumes were calculated using the same method as in Example 1.

[0056] Compound A was orally administered to mice in each group at a dose of 50 mg/kg (20 ml/kg), once a day for 14 days. The control group was not treated.

[0057] The tumor volume and body weight of each mouse were measured on days 3, 7, 10, and 14 after the start of Compound A administration. The changes in mean tumor volume in each group are shown in Table 2 and Fig. 2.

[0058] [Table 2]

Changes in mean tumor volume after initiation of compound A administration

Day 0 Day 3 Day 7 Day 10 Day 14 Control group (mm ³ ) 237.2 352.4 466.2 530.4 675.1 Compound A, group 50 mg/kg (mm ³ ) 234.1 267.0 338.8 380.8 403.4

Claims (25)

1. The use of 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide represented by formula (I) or a pharmacologically acceptable salt thereof for the treatment of breast cancer that has developed resistance to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and estrogen receptor antagonists, without combination with CDK4/6 inhibitors and estrogen receptor antagonists 2. The use according to claim 1, wherein the pharmacologically acceptable salt is 1,5-succinate. 3. The use according to claim 1 or 2, wherein the breast cancer is estrogen receptor positive. 4. The use according to any one of claims 1-3, wherein the breast cancer is human epidermal growth factor receptor type 2 (HER2) positive. 5. The use according to any one of claims 1-4, wherein the CDK4/6 inhibitor is one or more selected from the group consisting of palbociclib, abemaciclib and ribociclib. 6. The use according to claim 5, wherein the CDK4/6 inhibitor is palbociclib. 7. The use according to any one of claims 1 to 6, wherein the estrogen receptor antagonist is one or more selected from the group consisting of tamoxifen, fulvestrant and mepitiostane. 8. The use according to claim 7, wherein the estrogen receptor antagonist is fulvestrant. 9. The use according to any one of claims 1 to 8, wherein the breast cancer is locally advanced breast cancer, metastatic breast cancer, recurrent breast cancer or unresectable breast cancer. 10. The use according to any one of claims 1 to 9, wherein the breast cancer expresses fibroblast growth factor receptor (FGFR). 11. The use according to claim 10, wherein the FGFR is FGFR1, FGFR2 or FGFR3. 12. A method for treating breast cancer that has developed resistance to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and estrogen receptor antagonists, which comprises administering 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide represented by formula (I) or its pharmacologically acceptable salt at a dose of 25 mg to 500 mg per day to a patient in need thereof, without combination with CDK4/6 inhibitors and estrogen receptor antagonists. 13. The method according to claim 12, wherein the pharmacologically acceptable salt is 1,5-succinate. 14. The method according to claim 12 or 13, wherein the breast cancer is estrogen receptor positive. 15. The method according to any one of claims 12-14, wherein the breast cancer is human epidermal growth factor receptor type 2 (HER2) positive. 16. The method according to any one of claims 12-15, wherein the CDK4/6 inhibitor is one or more selected from the group consisting of palbociclib, abemaciclib and ribociclib. 17. The method of claim 16, wherein the CDK4/6 inhibitor is palbociclib. 18. The method according to any one of claims 12-17, wherein the estrogen receptor antagonist is one or more selected from the group consisting of tamoxifen, fulvestrant and mepitiostane. 19. The method of claim 18, wherein the estrogen receptor antagonist is fulvestrant. 20. The method according to any one of claims 12-19, wherein the breast cancer is locally advanced breast cancer, metastatic breast cancer, recurrent breast cancer, or unresectable breast cancer. 21. The method according to any one of claims 12-20, wherein the breast cancer expresses fibroblast growth factor receptor (FGFR). 22. The method of claim 21, wherein the FGFR is FGFR1, FGFR2, or FGFR3.