Combination of PI3k inhibitor and endocrine therapeutic drug and use thereof

Abstract

A combination of a PI3K inhibitor and an endocrine therapeutic drug, and use thereof. Specifically, the present invention relates to a combination of a PI3K inhibitor and an endocrine therapeutic drug, and use thereof for treating breast cancer, wherein the PI3K inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

Description

Combinations and uses of PI3K inhibitors and endocrine therapy drugs

[0001] Cross-references to related applications

[0002] This application claims priority to Chinese Patent Application No. 202411814370.9, filed on December 10, 2024. The entire contents of the aforementioned Chinese Patent Application are incorporated herein by reference. Technical Field

[0003] This disclosure pertains to the field of biomedicine, specifically relating to a combination of a PI3K inhibitor and an endocrine therapy drug, and their uses. Background Technology

[0004] Breast cancer is the most common malignant tumor among women worldwide. Advanced breast cancer seriously threatens the lives of patients. Among them, estrogen receptor-positive (HR+) / human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer is the most common subtype of advanced breast cancer. Endocrine therapy is one of the treatment methods for estrogen receptor-positive breast cancer. Treatment drugs include selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs). In addition, multiple studies have confirmed that CDK4 / 6 inhibitors combined with endocrine therapy can improve the prognosis of patients with HR+ / HER2- advanced breast cancer and have become the standard treatment regimen for these patients. Summary of the Invention

[0005] This disclosure aims to provide a combination of a PI3K inhibitor and an endocrine therapy drug and its use.

[0006] This disclosure provides the use of a combination of a PI3K inhibitor and an endocrine therapy drug in the preparation of a medicament for treating breast cancer, wherein the PI3K inhibitor is compound 1 or a pharmaceutically acceptable salt thereof;

[0007] This disclosure also provides the use of a combination of a PI3K inhibitor, an endocrine therapy agent, and a CDK4 / 6 inhibitor in the preparation of a medicament for treating breast cancer, wherein the PI3K inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

[0008] This disclosure also provides the use of a PI3K inhibitor in the preparation of a medicament for the treatment of breast cancer in combination with an endocrine therapy, wherein the PI3K inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

[0009] This disclosure also provides the use of a PI3K inhibitor in the preparation of a medicament for the treatment of breast cancer in combination with an endocrine therapy and a CDK4 / 6 inhibitor, wherein the PI3K inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

[0010] This disclosure also provides a method for treating breast cancer in a subject, the method comprising administering to the subject in need a therapeutically effective amount of a PI3K inhibitor and an endocrine therapy drug, wherein the PI3K inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

[0011] This disclosure also provides a method for treating breast cancer in a subject, the method comprising administering to the subject in need a therapeutically effective amount of a PI3K inhibitor, an endocrine therapy drug, and a CDK4 / 6 inhibitor, wherein the PI3K inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

[0012] This disclosure also provides a pharmaceutical combination product comprising a PI3K inhibitor and an endocrine therapy agent, optionally further comprising a CDK4 / 6 inhibitor, wherein the PI3K inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

[0013] This disclosure also provides a pharmaceutical combination product comprising a PI3K inhibitor, an endocrine therapy agent, and a CDK4 / 6 inhibitor, wherein the PI3K inhibitor is compound 1 or a pharmaceutically acceptable salt thereof.

[0014] In some implementations, the drug combination product may include:

[0015] (i) a pharmaceutical composition comprising a PI3K inhibitor, wherein the PI3K inhibitor is compound 1 or a pharmaceutically acceptable salt thereof; and

[0016] (ii) Instructions for the combined use of the PI3K inhibitor with an endocrine therapy.

[0017] In some implementations, the drug combination product may include:

[0018] (i) a pharmaceutical composition comprising a PI3K inhibitor, wherein the PI3K inhibitor is compound 1 or a pharmaceutically acceptable salt thereof; and

[0019] (ii) Instructions for the combined use of the PI3K inhibitor with endocrine therapy drugs and CDK4 / 6 inhibitors.

[0020] In some implementations, the drug combination product may be in the form of commercial packaging or a medicine box.

[0021] This disclosure also provides the use of the above-described pharmaceutical combination product in the preparation of a medicament for treating breast cancer.

[0022] In some embodiments, the endocrine therapy drug is an anti-estrogen drug, such as a selective estrogen receptor downregulator. In some embodiments, the endocrine therapy drug is fulvestrant.

[0023] In some embodiments, the CDK4 / 6 inhibitor is Dalpiciclib, Palbociclib, Trilaciclib, Abemaciclib, Ribociclib, Birociclib, Lerociclib, Culmerciclib, Fovinaciclib, Atirmociclib, Tibremciclib, Narazaciclib, Milciclib, Crozbaciclib, Voruciclib, Riviciclib, Inixaciclib, Roniciclib, or Auceliciclib. In some embodiments, the CDK4 / 6 inhibitor is Palbociclib. In some embodiments, the CDK4 / 6 inhibitor is Dalpiciclib. In some embodiments, the CDK4 / 6 inhibitor is Trilaciclib. In some embodiments, the CDK4 / 6 inhibitor is Abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is Ribociclib.

[0024] In some embodiments, the breast cancer is estrogen receptor-positive breast cancer. In some embodiments, the breast cancer is human epidermal growth factor receptor 2-negative breast cancer. In some embodiments, the breast cancer is estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer.

[0025] In some implementations, the breast cancer is triple-negative breast cancer.

[0026] In some embodiments, the breast cancer comprises a PIK3CA mutation. The PIK3CA mutation may include, but is not limited to, one or more of the following amino acid mutations: H1047D / I / L / N / P / Q / R / T / Y, E545A / D / G / K / L / Q / R / V, E542A / D / G / K / Q / R / V, Q546E / H / K / L / P / R, N345D / H / I / K / S / T / Y, C420R, M1043I / T / V, G1049A / C / D / R / S, E453A / D / G / K / Q / V, K111N / R / E, G106A / D / R / S / V, G118D, R88Q, H1048R. In some embodiments, the PIK3CA mutation includes one or more of the following amino acid mutations: E542K, E545K, Q546R, H1047L, H1047R.

[0027] In some implementations, the breast cancer comprises PIK3CA wild-type.

[0028] In some embodiments, the breast cancer is estrogen receptor-positive, human epidermal growth factor receptor 2-negative, PIK3CA-mutated breast cancer (e.g., locally advanced and / or metastatic breast cancer).

[0029] In some embodiments, the breast cancer is resistant to at least one endocrine therapy (e.g., an anti-estrogen drug). In some embodiments, the breast cancer is resistant to one or more of the following drugs: anastrozole, letrozole, exemestane, tamoxifen, toremifene, and fulvestrant. In some embodiments, the breast cancer is resistant to fulvestrant. For example, the breast cancer subject may be a subject who has developed resistance to fulvestrant after previous treatment.

[0030] In some embodiments, the breast cancer is resistant to at least one CDK4 / 6 inhibitor. In some embodiments, the breast cancer is resistant to one or more of the following CDK4 / 6 inhibitors: dalcirib, palbociclib, triasirib, abeciclib, and reboxiclib. In some embodiments, the breast cancer is resistant to palbociclib.

[0031] In some embodiments, the breast cancer is resistant to at least one of the following combinations: endocrine therapy (e.g., selective estrogen receptor modulators, selective estrogen receptor downregulators, aromatase inhibitors) and CDK4 / 6 inhibitors. In some embodiments, the breast cancer is resistant to one or more of the following combinations: endocrine therapy is anastrozole, letrozole, exemestane, tamoxifen, toremifene, or fulvestrant; and the CDK4 / 6 inhibitor is dalciglioide, palbociclib, triasiglioide, abeciclib, or reboxiclib. In some embodiments, the breast cancer is resistant to at least one of the following combinations: fulvestrant and CDK4 / 6 inhibitors. In some embodiments, the breast cancer is resistant to the combination of fulvestrant and palbociclib.

[0032] In some embodiments, the breast cancer is resistant to at least one chemotherapeutic agent. In some embodiments, the at least one chemotherapeutic agent is a microtubule inhibitor (e.g., paclitaxel, albumin-bound paclitaxel, docetaxel, vincristine, vinorelbine, vindesine), a dihydrofolate reductase inhibitor (e.g., pemetrexed, docetaxel, methotrexate), a thymidylate synthase inhibitor (e.g., 5-fluorouracil, tegafur, tegafur, carmoflurane, deoxyfluorouracil, difuranofuracil, gemcitabine, capecitabine, vinorelbine), a purine nucleotide tautomerase inhibitor (e.g., mercaptopurine, azathioprine, 6-thioguanine), or a nucleotide reductase inhibitor (e.g., hydroxychloroquine). The following are permitted: urea, DNA polymerase inhibitors (e.g., cytarabine), alkylating agents (e.g., nitrogen mustard, dacarbazine, semustine, carmustine, cyclophosphamide, temozolomide, ifosfamide), platinum complexes (e.g., cisplatin, carboplatin, nedaplatin, bicycloplatin, pyrplatin, oxaliplatin, miplatin, lobaplatin, levoplatin), and topoisomerase inhibitors (e.g., topotecan, irinotecan, topotecan, etoposide, teniposide, doxorubicin, epirubicin, daunorubicin, demethoxydaunorubicin, penoxorubicin, homoharringtonine, homoharringtonine).

[0033] In some implementations, the breast cancer is locally advanced and / or metastatic breast cancer.

[0034] In some implementations, the breast cancer is an unresectable and / or radiation-insensitive breast cancer.

[0035] In some implementations, the subjects are premenopausal or perimenopausal women.

[0036] In some embodiments, the subject has not been treated with a PI3K inhibitor prior to administration of the combination disclosed herein.

[0037] In this disclosure, the PI3K inhibitor, endocrine therapy drug, and optional CDK4 / 6 inhibitor may be administered simultaneously or sequentially.

[0038] In this disclosure, the PI3K inhibitors, endocrine therapy drugs, and optional CDK4 / 6 inhibitors can be administered by any suitable method, such as oral, intravenous, intramuscular, subcutaneous, or intravenous infusion. Depending on the administration method, the PI3K inhibitors, endocrine therapy drugs, and optional CDK4 / 6 inhibitors can be formulated into various conventional dosage forms, such as, but not limited to, tablets, capsules, granules, syrups, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, and injections. These dosage forms can be prepared using techniques known in the art.

[0039] In some embodiments, the PI3K inhibitor (compound 1 or a pharmaceutically acceptable salt thereof) is administered orally.

[0040] The PI3K inhibitor can be administered at a fixed dose or based on the individual's weight or body surface area.

[0041] In some embodiments, the single-dose administration of the PI3K inhibitor (compound 1 or a pharmaceutically acceptable salt thereof) is from 0.01 mg to 1000 mg, for example 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 6 0mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, or 1000mg. In some embodiments, the single dose of the PI3K inhibitor (compound 1 or a pharmaceutically acceptable salt thereof) is from 5 mg to 300 mg.

[0042] In some embodiments, the single-dose administration of the PI3K inhibitor (compound 1 or a pharmaceutically acceptable salt thereof) is from 0.01 mg / kg to 100 mg / kg, for example 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg. / kg, 1mg / kg, 2mg / kg, 3mg / kg, 4mg / kg, 5mg / kg, 6mg / kg, 7mg / kg, 8mg / kg, 9mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, 100mg / kg, based on the body weight of the individual receiving the medication. In some embodiments, the single-dose administration of the PI3K inhibitor (compound 1 or a pharmaceutically acceptable salt thereof) is from 0.1mg / kg to 50mg / kg.

[0043] In some embodiments, the PI3K inhibitor (compound 1 or a pharmaceutically acceptable salt thereof) may be administered once daily (QD), twice daily (BID), three times daily (TID), four times daily (QID), once weekly (QW), twice weekly (BIW), three times weekly (TIW), once every two weeks (Q2W), once every three weeks (Q3W), or once monthly. In some embodiments, the PI3K inhibitor is administered once daily. In some embodiments, the PI3K inhibitor is administered twice daily. In some embodiments, the PI3K inhibitor is administered three times daily.

[0044] In some embodiments, the PI3K inhibitor (compound 1 or a pharmaceutically acceptable salt thereof) is administered in a single dose of 5 mg, 10 mg, 20 mg, 40 mg, 75 mg, 125 mg, 200 mg, 250 mg or 300 mg once daily.

[0045] In some embodiments, the PI3K inhibitor (compound 1 or a pharmaceutically acceptable salt thereof) is administered in a single dose of 40 mg, 75 mg, 100 mg, 125 mg or 150 mg, twice daily.

[0046] In some embodiments, the PI3K inhibitor (compound 1 or a pharmaceutically acceptable salt thereof) is administered in a single dose of 75 mg twice daily.

[0047] In some embodiments, the PI3K inhibitor (compound 1 or a pharmaceutically acceptable salt thereof) is administered in a single dose of 100 mg twice daily.

[0048] In some embodiments, the PI3K inhibitor (compound 1 or a pharmaceutically acceptable salt thereof) is administered in a single dose of 125 mg twice daily.

[0049] When compound 1 is administered in the form of its pharmaceutically acceptable salt, the dosage is equivalent to that of the free form of compound 1.

[0050] In some implementations, the endocrine therapy drug (e.g., fulvestrant) is administered via intravenous injection, intramuscular injection, subcutaneous injection, or intravenous infusion.

[0051] In some embodiments, the single-dose administration of the endocrine therapy drug (e.g., fulvestrant) is from 0.01 mg to 1000 mg, for example, 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, or 1000mg. In some embodiments, the endocrine therapy drug is fulvestrant, with a single dose of 500mg.

[0052] In some embodiments, the single-dose administration of the endocrine therapy drug (e.g., fulvestrant) is from 0.01 mg / kg to 100 mg / kg, for example 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, based on the individual's body weight.

[0053] In some embodiments, the endocrine therapy drug (e.g., fulvestrant) may be administered once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, three times weekly, once every two weeks, once every three weeks, or once monthly.

[0054] In some embodiments, the endocrine therapy drug is administered at the standard dose and frequency when used alone, such as the recommended dose and frequency in the drug's package insert (e.g., fulvestrant is recommended at a dose of 500 mg once on days 1, 15, and 29, and then monthly thereafter). In some embodiments, the endocrine therapy drug may be administered at 5% to 95% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%) of the standard dose when used alone.

[0055] In some embodiments, the endocrine therapy drug is fulvestrant, administered once on day 1 and day 15 of the first 28-day cycle, with a single dose of 500 mg; if one or more additional 28-day cycles are included after the first 28-day cycle, fulvestrant is administered once on day 1 of each additional 28-day cycle, with a single dose of 500 mg.

[0056] In some implementations, the CDK4 / 6 inhibitor (e.g., palbociclib) is administered orally.

[0057] In some embodiments, the single-dose administration of the CDK4 / 6 inhibitor (e.g., palbociclib) is from 0.01 mg to 1000 mg, for example, 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg. The dosages are 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg. In some embodiments, the CDK4 / 6 inhibitor is palbociclib, with a single dose of 125 mg.

[0058] In some embodiments, the single-dose administration of the CDK4 / 6 inhibitor (e.g., palbociclib) is from 0.01 mg / kg to 100 mg / kg, for example 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, and 0.9 mg / kg. 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, based on the individual's body weight.

[0059] In some embodiments, the CDK4 / 6 inhibitor (e.g., palbociclib) may be administered once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, three times weekly, once every two weeks, once every three weeks, or once monthly. In some embodiments, the CDK4 / 6 inhibitor (e.g., palbociclib) may be administered once daily.

[0060] In some embodiments, the CDK4 / 6 inhibitor is administered at the standard dose and frequency when the anti-CDK4 / 6 inhibitor is used alone, such as the recommended dose and frequency in the drug's package insert (e.g., palbociclib's recommended dose is 125 mg / dose for 21 consecutive days, followed by a 7-day break, with 28 days constituting one treatment cycle). In some embodiments, the CDK4 / 6 inhibitor may be administered at 5% to 95% (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%) of the standard dose when the CDK4 / 6 inhibitor is used alone.

[0061] In some implementations, the CDK4 / 6 inhibitor is palbociclib, and a 28-day treatment cycle is performed, with palbociclib administered once daily on days 1–21 of the 28-day cycle, at a single dose of 125 mg.

[0062] The combinations disclosed herein can be administered for one or more cycles, wherein each cycle can be longer than one week, such as one week, two weeks, three weeks, four weeks, one month, two months, three months, four months, five months, six months, one year, two years, or longer; optionally, the duration of each cycle can be the same or different, and the interval between each cycle can be the same or different. In some embodiments, the combinations disclosed herein can be administered for one or more cycles, wherein each cycle is 28 days. Within any treatment cycle, the dosage and frequency of administration of each therapeutic agent in the combination can be adjusted as needed; for example, after using an initial dose, subsequent doses can be 10% to 300% of the initial dose, such as 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%.

[0063] In some embodiments, the combination disclosed herein comprises compound 1 or a pharmaceutically acceptable salt thereof and fulvestrant, in a treatment cycle of 28 days:

[0064] (a) Compound 1 or a pharmaceutically acceptable salt thereof may be administered daily on days 1–28 of the first 28-day cycle, with the single dose and frequency as described above;

[0065] (b) Administer fulvestrant once on day 1 and day 15 of the first 28-day cycle, with a single dose of 500 mg.

[0066] Optionally, one or more additional 28-day cycles may be included after the first 28-day cycle, wherein:

[0067] (a) Apply compound 1 or a pharmaceutically acceptable salt thereof daily on days 1–28 of each additional 28-day cycle, with the single dose and frequency as described above;

[0068] (b) Administer fulvestrant once on day 1 of each additional 28-day cycle, with a single dose of 500 mg.

[0069] In some embodiments, the combination of this disclosure comprises compound 1 or a pharmaceutically acceptable salt thereof, fulvestrant, and palbociclib, in a treatment cycle of 28 days:

[0070] (a) Compound 1 or a pharmaceutically acceptable salt thereof may be administered daily on days 1–28 of the first 28-day cycle, with the single dose and frequency as described above;

[0071] (b) Administer fulvestrant once on day 1 and day 15 of the first 28-day cycle, with a single dose of 500 mg.

[0072] (c) Palbociclib was administered once daily on days 1–21 of the first 28-day cycle, with a single dose of 125 mg.

[0073] Optionally, one or more additional 28-day cycles may be included after the first 28-day cycle, wherein:

[0074] (a) Apply compound 1 or a pharmaceutically acceptable salt thereof daily on days 1–28 of each additional 28-day cycle, with the single dose and frequency as described above;

[0075] (b) Administer fulvestrant once on day 1 of each additional 28-day cycle, with a single dose of 500 mg.

[0076] (c) Palbociclib is administered once daily on days 1–21 of each additional 28-day cycle, with a single dose of 125 mg.

[0077] In some implementations, the combination of this disclosure can achieve synergistic effects.

[0078] In some embodiments, administration of the combinations disclosed herein to a subject with breast cancer results in complete tumor remission. In some embodiments, administration of the combinations disclosed herein to a subject with breast cancer results in a reduction in tumor volume of 30% or more, such as 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more. The reduction in tumor volume can be measured by any method known in the art, such as X-ray, positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), cytological, histological, or molecular genetic analysis.

[0079] This disclosure also provides the use of a PI3K inhibitor in the preparation of a medicament for treating breast cancer (e.g., the use of a PI3K inhibitor as the sole active ingredient in the preparation of a medicament for treating breast cancer), wherein the PI3K inhibitor is compound 1 or a pharmaceutically acceptable salt thereof; the breast cancer may be as defined above; and the administration method, dosage, and frequency of the PI3K inhibitor may be as defined above.

[0080] This disclosure also provides a method for treating breast cancer in a subject, the method comprising administering a therapeutically effective amount of a PI3K inhibitor to the subject in need, wherein the PI3K inhibitor is compound 1 or a pharmaceutically acceptable salt thereof; the breast cancer may be as defined above; and the manner, dosage and frequency of administration of the PI3K inhibitor may be as defined above.

[0081] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense.

[0082] The terms "drug combination product" or "combination" can refer to a fixed combination of products administered in a single dosage unit (e.g., a single dosage form containing all active pharmaceutical ingredients) or a kit, or a combination of a drug and a package insert indicating that the drug can be used in combination with one or more other drugs. For example, in some embodiments, the combinations disclosed herein may include: a pharmaceutical composition containing a PI3K inhibitor; and a package insert indicating that the PI3K inhibitor is used in combination with an endocrine therapy drug, or an endocrine therapy drug and a CDK4 / 6 inhibitor, for the treatment of breast cancer. In some embodiments, the combinations disclosed herein may include: (i) a first pharmaceutical composition containing a PI3K inhibitor; and (ii) a second pharmaceutical composition containing an endocrine therapy drug; optionally further including (iii) a third pharmaceutical composition containing a CDK4 / 6 inhibitor (the first, second, and third pharmaceutical compositions are each separate pharmaceutical compositions). In some embodiments, the combinations disclosed herein may include: a single pharmaceutical composition containing a PI3K inhibitor, an endocrine therapy drug, and a CDK4 / 6 inhibitor (i.e., a single dosage form containing a PI3K inhibitor, an endocrine therapy drug, and a CDK4 / 6 inhibitor).

[0083] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for exposure to mammalian (especially human) tissues within the limits of reasonable medical judgment, without excessive toxicity, irritation, allergic reactions, and other problematic complications, and with a reasonable benefit / risk ratio.

[0084] The term "pharmaceutically acceptable salt" refers to a salt formed by a compound with a relatively non-toxic, pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as formic acid, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Some compounds contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0085] The term "treatment" refers to the application of one or more pharmaceutical substances to a person suffering from or having symptoms of a disease in order to cure, alleviate, reduce, alter, treat, improve, enhance, or affect the disease or its symptoms.

[0086] The term "therapeutic effective amount" refers to the amount of medicine that is sufficient to effectively treat a disease or condition when administered to a subject. The therapeutic effective amount of medicine administered to a subject will depend on various factors, such as the given drug or compound, the drug formulation, the route of administration, the type of disease, the condition, the age and condition of the subject being treated, etc., but can still be routinely determined by those skilled in the art.

[0087] The term "subject" refers to both mammals and non-mammals. Mammals include any member of the mammalian class, including but not limited to: humans; non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs; and so on. Examples of non-mammals include, but are not limited to, birds. The term "subject" is not limited to a specific age or sex. In some implementations, the subject is a human.

[0088] The term "simultaneous or sequential administration" refers to the simultaneous or sequential administration of two or more drugs within a single dosing cycle (e.g., within 4 weeks, 3 weeks, 2 weeks, 1 week, or 24 hours) at regular intervals, so that they can work together to achieve the desired therapeutic effect. The manner of administration for each drug can be the same or different, and the frequency / cycle of administration can be the same or different.

[0089] The terms "endocrine therapy" or "endocrine treatment" refer to therapeutic agents that treat breast cancer by regulating and altering the body's endocrine environment and hormone levels, including but not limited to selective estrogen receptor modulators, selective estrogen receptor downregulators, and aromatase inhibitors.

[0090] The term "anti-estrogenic drug" refers to therapeutic agents that inhibit or weaken the effects of estrogen, including but not limited to selective estrogen receptor modulators and selective estrogen receptor downregulators.

[0091] The term "CDK4 / 6 inhibitor" refers to any compound that can inhibit the activity of CDK4 and / or CDK6.

[0092] The term "synergy" means that the combined effect achieved using this disclosure is greater than the sum of the effects of using them individually.

[0093] The term "drug resistance" refers to the tolerance of cancer patients or cancer cells to the effects of a drug. For example, after cancer patients or cancer cells develop resistance to a particular drug, the therapeutic effect of that drug significantly decreases. Cancer patients or cancer cells may acquire drug resistance through a series of mechanisms, including mutations or overexpression of the drug target, drug inactivation, or elimination of the drug from the cells. Drug resistance can be classified into primary resistance and acquired resistance based on its cause. Primary resistance refers to cancer patients or cancer cells being insensitive to the drug at the start of treatment, while acquired resistance refers to cancer patients or cancer cells that were initially sensitive to the drug becoming insensitive after repeated administration. Drug resistance in cancer patients includes cancers that do not respond to drug treatment, cancers that progress during drug treatment, cancer recurrence, cancer relapse, and refractory cancers. Recurrence can refer to the reappearance of cancer at the original site or a new site after treatment.

[0094] The names of endocrine therapy drugs and CDK4 / 6 inhibitors listed in this disclosure include both the free form of the active ingredient and its pharmaceutically acceptable salt form. For example, dalcirib includes, but is not limited to, the free dalcirib compound and its clinically commonly used dalcirib ethanesulfonate; triasicilrib includes, but is not limited to, the free triasicilrib compound and its clinically commonly used triasicilrib hydrochloride; and reboxil includes, but is not limited to, the free reboxilrib compound and its clinically commonly used reboxilrib succinate.

[0095] Any compound (e.g., compound 1) and therapeutic agent mentioned in this disclosure also include its tautomers and isotopic derivatives. All forms of any compound (e.g., compound 1), therapeutic agent, isotopic derivative, pharmaceutically acceptable salt, including various solid and mixture forms thereof, such as crystalline, amorphous, solvate (e.g., hydrate), or any mixture thereof, are included within the scope of this disclosure.

[0096] Without violating common sense in the field, the various implementation schemes and preferred conditions described herein can be combined arbitrarily to obtain various preferred examples of this disclosure.

[0097] The positive advancements of this disclosure lie in providing a combination of a PI3K inhibitor and an endocrine therapy drug ± a CDK4 / 6 inhibitor, and its use therein. This combination has demonstrated excellent efficacy and safety in the treatment of breast cancer patients. Attached Figure Description

[0098] Figure 1 shows the tumor growth curves for each group of mice. Data points represent the mean body weight, and error bars represent the standard error. * represents p < 0.05, ** represents p < 0.01, and *** represents p < 0.001.

[0099] Figure 2 shows the changes in body weight of mice in each group. Data points represent the average tumor volume, and error bars represent standard errors.

[0100] Figure 3 shows the percentage change in body weight (%) for each group of mice. The percentage change in body weight was calculated based on the mice's body weight at the start of drug administration. Data points represent the average percentage change in body weight within each group, and error bars represent standard errors. Detailed Implementation

[0101] The present disclosure is further illustrated below by way of embodiments, but these embodiments are not intended to limit the scope of the present disclosure. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected in accordance with the product instructions.

[0102] In the following examples, the raw materials and reagents used are commercially available, or can be prepared by those skilled in the art by referring to known methods or by conventional modifications based on known methods.

[0103] Example 1: Efficacy of compound 1 alone, in combination with endocrine therapy, and in combination with endocrine therapy and CDK4 / 6 inhibitors in a BALB / c nude mouse model of MCF-7 human breast cancer cell subcutaneous xenograft tumors.

[0104] Experimental materials:

[0105] Test samples: Compound 1, BYL-719 (Alpelisib), fulvestrant, palbociclib.

[0106] Experimental animals: BALB / c nude mice, aged 6–8 weeks, weighing 18–20 grams, purchased from Shanghai Lingchang Biotechnology Co., Ltd.

[0107] Cells: Human breast cancer cells MCF-7, purchased from the European Certified Cell Culture Collection (ECACC), catalog number: 86012803.

[0108] Experimental methods:

[0109] 1. Preparation of test sample

[0110] Compound 1: 2.5 mg / mL, in an aqueous solution of 0.5% methylcellulose 400 cp + 0.2% Tween 80.

[0111] BYL-719: 2.5 mg / mL, solvent is an aqueous solution of 0.5% methylcellulose 400cp + 0.2% Tween 80.

[0112] Fulvestrant: 20 mg / mL, solvent is Cremophor EL (Macklin, C804845).

[0113] Palbociclib: 5 mg / mL, solvent is 50 mM sodium lactate aqueous solution (pH = 4.03).

[0114] 2. Cell culture, inoculation, and experimental grouping

[0115] MCF-7 cells were cultured in vitro in a monolayer under the following conditions: EMEM medium (ATCC, catalog number 30-2003) supplemented with 10% fetal bovine serum (Corning, catalog number 35-081-CV), 1% non-essential amino acids (Non-Essential Amino Acid, Gibco, catalog number 11140-050), 2 mM L-glutamine, and 1% Antibiotic-Antimycotic (Gibco, catalog number 15240-062) in a 37°C incubator containing 5% CO2. Cells were passaged twice a week after digestion with 0.25% Trypsin-EDTA (Gibco, catalog number 25200-072). When the cells reached the exponential growth phase, they were harvested, counted, and seeded (3 days prior to tumor cell seeding, 0.36 mg / tablet of estrogen sustained-release tablets were subcutaneously injected into mice).

[0116] 0.2 mL of MCF-7 tumor cells (containing 10 × 10⁶ cells) were added. 6Cells were subcutaneously inoculated into the upper right back of mice, with the cell suspension consisting of PBS and Matrigel (volume ratio 1:1). On day 7 post-inoculation, the average tumor volume reached 168 mmHg. 3 At that time, mice were randomly divided into groups based on tumor volume and body weight, and drug administration was initiated. The number of animals in each group and the administration regimen are shown in Table 1.

[0117] Table 1: Grouping and Dosing Regimens of Experimental Animals

[0118] Note: Vehicle administration is 0.5% MC (400 cp) + 0.2% Tween 80 aqueous solution. The day of grouping is recorded as D0, and administration begins on D0.

[0119] 3. Tumor measurement and experimental indicators

[0120] The tumor's long and short diameters were measured twice a week using calipers, and the tumor volume was calculated using the formula: V = 0.5a × b 2 , where a and b represent the long and short diameters of the tumor, respectively.

[0121] The antitumor efficacy of the compounds was evaluated using TGI (%) or relative tumor proliferation rate T / C (%).

[0122] The formula for calculating the relative tumor proliferation rate T / C (%) is: T / C% = T RTV / C RTV ×100% (T) RTV : Mean RTV in the treatment group; C RTV (Mean RTV of the negative control group). First, the relative tumor volume (RTV) of each mouse in each group was calculated based on the tumor measurement results. The calculation formula is RTV = V t / V0. Where V0 is the tumor volume measured in a single mouse at the time of group drug administration (i.e., D0), V t This represents the tumor volume of a single mouse at a given measurement. Then, based on the RTV of all mice in the group, the mean RTV for that group is calculated, which is T. RTV (or C) RTV ). T RTV With C RTV Take data from the same day.

[0123] TGI (%) reflects the tumor growth inhibition rate. TGI (%) = [1 - (T...] i -T0) / (V i -V0)]×100%, where T i V represents the average tumor volume of a specific treatment group on a given day, where T0 represents the average tumor volume of the treatment group at the start of treatment; i For a certain day (with T)i On the same day, the average tumor volume of the solvent control group was V0, which is the average tumor volume of the solvent control group at the start of drug administration.

[0124] 4. Data Processing

[0125] Statistical analysis was performed using GraphPad Prism 9 software, based on tumor volume data at the end of the trial. Comparisons between two groups were analyzed using the t-test, and comparisons between three or more groups were analyzed using one-way ANOVA (Dunnett's multiple comparison test). A p-value < 0.05 was considered statistically significant.

[0126] 5. Experimental Results

[0127] The tumor volumes of mice in each group at different time points are shown in Table 2, and the tumor growth curves are shown in Figure 1.

[0128] Table 2: Tumor volume of mice in each group at different time points

[0129] The tumor-suppressing effects of each group of test substances are shown in Table 3.

[0130] Table 3: Antitumor efficacy of the test substance against the subcutaneous xenograft tumor model MCF-7 (calculated based on D28 tumor volume).

[0131] After 28 days of treatment with Vehicle, Compound 1, BYL-719, fulvestrant, and palbociclib, the mean tumor volume in the solvent control group was 517 ± 56 mm. 3 The mean tumor volume in the compound 1 (25 mg / kg) group was 148 ± 23 mm. 3 The TGI was 105.83%, which was significantly different from the solvent control group (p<0.01). The mean tumor volume in the BYL-719 (25 mg / kg) group was 236 ± 34 mm. 3 The TGI of fulvestrant was 80.45%, which was statistically different from the solvent control group (p<0.05), indicating a weaker tumor-suppressing effect compared to compound 1 at the same dose. There was no statistically significant difference between the fulvestrant monotherapy group (200 mg / kg) and the solvent control group. The fulvestrant combined with compound 1, fulvestrant combined with BYL-719, and fulvestrant combined with palbociclib showed highly significant differences compared to the solvent control group (p<0.001). The efficacy of fulvestrant combined with compound 1 (TGI 118.89%) was superior to that of fulvestrant combined with BYL-719 (TGI 111.28%) and fulvestrant combined with palbociclib (TGI 109.27%). The mean tumor volume in the fulvestrant, compound 1, and palbociclib triple therapy group was 42±4 mm. 3The TGI was 136.02%, which was significantly different from the solvent control group (p<0.001), and statistically different from both the compound 1 monotherapy group and the compound 1 + fulvestrant combination group (p<0.05).

[0132] The combined effect of drugs was evaluated using the Jin Zhengjun formula (Jin Zhengjun. Additive effects of combined medications [J]. Chinese Journal of Pharmacology, 1980, 1(2):70-75, the full text of which is incorporated herein by reference): Q = E A+B / (E A +E B -E A ×E B ), where E A+B For the combined effects of medication, E A and E B The effects of drug A and drug B are shown separately; Q = 0.85–1.15 indicates the simple additive effect of the two drugs, Q > 1.15 indicates synergistic effect, and Q < 0.85 indicates antagonistic effect. The combined effect of fulvestrant, compound 1, and palbociclib was calculated using TGI (%) data from groups G2, G7, and G8. Q = 1.368 indicates a synergistic effect among fulvestrant, compound 1, and palbociclib.

[0133] The effects of each test substance on the body weight of female BALB / c nude mice in the subcutaneous xenograft MCF-7 tumor model are shown in Figures 2 and 3. During the administration period, some animals experienced fluctuations in body weight due to estrogen inoculation, but the overall average body weight change did not exceed 10% in any group, and the body weight changes of the experimental animals before and after treatment were not significant.

[0134] Example 2: A phase I / Ib clinical study of the safety, tolerability, pharmacokinetic characteristics, and preliminary efficacy of compound 1 capsules as monotherapy in patients with advanced solid tumors, and in combination with fulvestrant with or without palbociclib in patients with PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER-2)-negative locally advanced or metastatic breast cancer.

[0135] Compound 1 single-drug dose escalation phase

[0136] This study aims to enroll patients with advanced solid tumors (including breast cancer) who have failed standard treatment. All participants will undergo a screening period, a treatment period (28-day cycle), a safety follow-up period, and a long-term follow-up period.

[0137] Compound 1 can be escalated to 5 mg, 10 mg, 20 mg, 40 mg, 75 mg, 125 mg, 200 mg, 250 mg, and 300 mg, administered once daily (QD). During dose escalation, the dose escalation range, dosage for each dose group, and dosing frequency may be adjusted based on safety evaluations, preliminary efficacy, and pharmacokinetic (PK) data. This includes, but is not limited to, adjusting the subsequent dosing frequency to twice daily (BID), with pre-set BID dose groups of 40 mg BID, 75 mg BID, 100 mg BID, 125 mg BID, and 150 mg BID; and potentially adding intermediate doses, not limited to a single dose group.

[0138] Treatment period: Cycle 1 begins with continuous dosing (QD or BID) to each subject for 28 days as one dosing cycle, until the subject's disease progresses, becomes intolerably toxic, or other conditions require discontinuation of treatment.

[0139] Compound 1 monotherapy dose expansion phase

[0140] This study investigates the safety, tolerability, and preliminary efficacy of a safe and probable effective dose during the monotherapy escalation phase in a larger number of subjects. The intended enrollees are patients with advanced solid tumors exhibiting PIK3CA gene mutations who have failed standard treatment.

[0141] Compound 1 combined dose escalation phase

[0142] The study included compound 1 in combination with fulvestrant (Group A) and compound 1 in combination with fulvestrant and palbociclib (Group B).

[0143] The study will enroll patients with PIK3CA-mutated, HR+ / HER2- locally advanced or metastatic breast cancer who are ineligible for curative surgery or radiotherapy. All participants will undergo a screening period, a treatment period (28 days per dosing cycle), a safety follow-up period, and a long-term follow-up period.

[0144] The starting dose of combination therapy will be determined based on the pharmacokinetic, safety, and preliminary efficacy data of compound 1 as a single agent. The starting dose of compound 1 in groups A and B will be based on the proven safe dose of the single agent and may be lower than the pre-specified recommended dose of the single agent.

[0145] Treatment period: Subjects received a specific dose of compound 1 orally continuously. Fulvestrant was administered at a dose of 500 mg, once intramuscularly on days 1 and 15 of the first cycle, followed by once intramuscularly on day 1 of each subsequent cycle (≥Cycle 2). Palbociclib was administered orally at a dose of 125 mg once daily for 21 consecutive days, followed by a 7-day break. All medications were administered in 28-day cycles until disease progression, intolerance, or other conditions requiring discontinuation of treatment occurred in the subject.

[0146] Efficacy evaluation was based on RECIST v1.1 criteria, assessing objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). In addition, the type, frequency, duration, and severity of adverse events were assessed.

[0147] Preliminary test results:

[0148] As of November 25, 2025, a total of 52 subjects were enrolled for compound 1 monotherapy (3 patients received 5 mg QD; 3 patients received 10 mg QD, 3 patients received 20 mg QD, 3 patients received 40 mg QD, 4 patients received 40 mg BID, 7 patients received 75 mg BID, 22 patients received 100 mg BID, and 7 patients received 125 mg BID). These included 34 patients with PIK3CA-mutated, HR+, HER2- breast cancer and 6 patients with PIK3CA-mutated triple-negative breast cancer (TNBC). The remaining patients had PIK3CA wild-type breast cancer. 31 patients who received monotherapy underwent at least one post-baseline tumor assessment. In the population receiving an effective dose of 75 mg BID or higher, the ORR was 37.5% (6 / 16), and the DCR was 62.5% (10 / 16), as shown in Table 4 below.

[0149] Table 4: Efficacy data of compound 1 monotherapy (not limited to PIK3CA mutation)

[0150] One TNBC patient and one HR-positive patient who received 75 mg BID monotherapy also achieved confirmed partial responses (PR) with significant depth of response (target lesions reduced by more than 50% from baseline).

[0151] Nineteen patients with PIK3CA-mutated, HR+, HER2- breast cancer completed at least one tumor assessment. Their median prior lines of anti-tumor therapy were three, and 16 patients had received CDK4 / 6 inhibitor therapy. The overall objective response rate (ORR) was 36.8% (7 / 19). In the 75 mg BID or higher dose group, 14 patients underwent tumor assessment, with an ORR of 35.7% (5 / 14) and a disease control rate (DCR) of 57.1% (8 / 14), as shown in Table 5 below.

[0152] Table 5: Efficacy data of compound 1 monotherapy in subjects with PIK3CA-mutated, HR+, HER2- breast cancer.

[0153] As of November 25, 2025, a total of 10 subjects (3 with 75 mg BID and 7 with 100 mg BID) were enrolled in the treatment of compound 1 in combination with fulvestrant. All of them were PIK3CA-mutated, HR+, HER2- breast cancer patients who had previously received at least one first-line systemic therapy. Among them, 6 subjects underwent at least one post-baseline tumor assessment, of which 4 were assessed as PR, with an overall ORR of 66.7% (4 / 6). The ORR in the 75 mg BID combination group was 33.3% (1 / 3), and the ORR in the 100 mg BID combination group was 100.0% (3 / 3). Information on the 4 subjects who achieved PR after treatment is shown in Table 6 below.

[0154] Table 6: Four subjects who achieved partial response (PR) after treatment with compound 1 in combination with fulvestrant

[0155] No SAEs occurred with Compound 1 as a monotherapy or in combination therapy. Common TRAEs include hyperglycemia, oral mucositis, rash, and gastrointestinal adverse events (such as abdominal discomfort, nausea, vomiting, and loss of appetite), which can be controlled or relieved with active intervention.

[0156] Preliminary trial results showed that compound 1 as a monotherapy was effective in treating both PIK3CA-mutated and PIK3CA wild-type breast cancer patients. The efficacy was significantly enhanced when compound 1 was combined with fulvestrant. It also showed efficacy in breast cancer patients previously treated with CDK4 / 6 and endocrine therapy. Compound 1 demonstrated good safety in the trial.

[0157] Based on the obtained trial results, we consider expanding the study to include patients with wild-type, HR+, HER2- breast cancer who have PIK3CA in combination with compound 1 for further investigation. Additionally, we may add reboxil, abecilibil, or dalsicilib as CDK4 / 6 inhibitors in combination with compound 1 and fulvestrant.

[0158] While specific embodiments of this disclosure have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of this disclosure. Therefore, the scope of protection of this disclosure is defined by the appended claims.

Claims

1. Use of a combination of a PI3K inhibitor and an endocrine therapy agent in the preparation of a medicament for treating breast cancer, wherein the PI3K inhibitor is compound 1 or a pharmaceutically acceptable salt thereof; 2. Use of a combination of a PI3K inhibitor, an endocrine therapy agent, and a CDK4 / 6 inhibitor in the preparation of a medicament for treating breast cancer, wherein the PI3K inhibitor is compound 1 or a pharmaceutically acceptable salt thereof; 3. The use as described in claim 1 or 2, characterized in that, The endocrine therapy drug is an anti-estrogen drug.

4. The use as described in any one of claims 1–3, characterized in that, The endocrine therapy drug is a selective estrogen receptor downregulator.

5. The use as described in any one of claims 1–4, characterized in that, The endocrine therapy drug is fulvestrant.

6. The use as described in any one of claims 2–5, characterized in that, The CDK4 / 6 inhibitors are Dalpiciclib, Palbociclib, Trilaciclib, Abemaciclib, Ribociclib, Birociclib, Lerociclib, Culmerciclib, Fovinaciclib, Atirmociclib, Tibremciclib, Narazaciclib, Milciclib, Crozbaciclib, Voruciclib, Riviciclib, Inixaciclib, Roniciclib, or Auceliciclib.

7. The use as described in any one of claims 2–5, characterized in that, The CDK4 / 6 inhibitor is palbociclib.

8. The use as described in any one of claims 1–7, characterized in that, The breast cancer mentioned is estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer.

9. The use as described in any one of claims 1–7, characterized in that, The breast cancer mentioned is triple-negative breast cancer.

10. The use as described in any one of claims 1–9, characterized in that, The breast cancer contained a PIK3CA mutation.

11. The use as described in any one of claims 1–9, characterized in that, The breast cancer described includes PIK3CA wild-type.

12. The use as described in any one of claims 1–11, characterized in that, The breast cancer in question is locally advanced and / or metastatic breast cancer.

13. Use of a PI3K inhibitor in the preparation of a medicament for the treatment of breast cancer in combination with an endocrine therapy, wherein the PI3K inhibitor, the endocrine therapy, and the breast cancer are as described in any one of claims 1–12.

14. Use of a PI3K inhibitor in the preparation of a medicament for the treatment of breast cancer in combination with an endocrine therapy agent and a CDK4 / 6 inhibitor, wherein the PI3K inhibitor, the endocrine therapy agent, the CDK4 / 6 inhibitor, and the breast cancer are as described in any one of claims 2–12.

15. A pharmaceutical combination product comprising a PI3K inhibitor and an endocrine therapy agent, optionally further comprising a CDK4 / 6 inhibitor; said PI3K inhibitor, endocrine therapy agent and CDK4 / 6 inhibitor as described in any one of claims 1–12.

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