Combination therapy for the treatment of breast cancer

Abstract

A combination therapy comprising enoxacin, palbociclib, and fulvestrant is provided, along with a method for treating locally advanced or metastatic breast cancer with PIC3CA mutations, hormone receptor-positive (HR+), and HER2-negative (HER2-), the method comprising administering therapeutically effective amounts of enoxacin, palbociclib, and fulvestrant. The combination therapy produced statistically significant and clinically meaningful improvements in comparable patients compared to administration of palbociclib and fulvestrant alone.

Description

Cross-reference to related applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 606,014, filed December 4, 2023; U.S. Provisional Patent Application No. 63 / 607,531, filed December 7, 2023; U.S. Provisional Patent Application No. 63 / 653,783, filed May 30, 2024; U.S. Provisional Patent Application No. 63 / 705,007, filed October 8, 2024; and U.S. Provisional Patent Application No. 63 / 713,780, filed October 30, 2024; the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] This invention relates to a combination of inavolisib, palbociclib, and fulvestrant for the treatment of advanced hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer with PIK3CA mutation. Background Technology

[0003] Globally, breast cancer is the second most common invasive malignancy in women and the most common cause of cancer-related death, with a 5-year survival rate of approximately 15% after a metastatic diagnosis.

[0004] Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that, upon activation by growth factor receptors and integrins, regulates cell proliferation, survival, and migration. PI3K catalyzes the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to produce phosphatidylinositol-3,4,5-triphosphate (PIP3), which is a second messenger involved in the phosphorylation of other components in the AKT and AKT / mTOR pathways. Up to 70% of breast cancers exhibit some form of molecular aberration in the PI3K / AKT / mTOR pathway. PIK3CA Activation of mutations in the p110α subunit encoding PI3K is very common in breast cancer and solid tumor malignancies.

[0005] Hormone receptor (HR) positive breast cancer is the most common type of breast cancer. The defining characteristic of HR-positive breast cancer is that its tumor cells have receptors that attach to one or two hormones (estrogen or progesterone) that promote tumor growth. People diagnosed with HR-positive metastatic breast cancer often face the risk of disease progression and treatment side effects, creating a need for additional treatment options. The PI3K signaling pathway is often dysregulated in HR-positive breast cancer, typically attributed to activated PIK3CA mutations, which have been identified as a potential mechanism for resistance to endocrine therapy and CDK4 / 6 inhibitors. Summary of the Invention

[0006] This disclosure provides a combination therapy comprising inaliprine, palbociclib, and fulvestrant for the treatment of breast cancer, such as PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer.

[0007] On the one hand, the combination therapy comprising inaliprine, palbociclib, and fulvestrant described in this article produced statistically significant and clinically meaningful improvements in patients with breast cancer (e.g., PIK3CA-mutated / mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer) compared to administration of palbociclib and fulvestrant alone to comparable patients (excluding inaliprine).

[0008] This disclosure further provides a method for treating patients with hormone receptor-positive and HER2-negative (HR+ / HER2-) locally advanced or metastatic breast cancer, comprising administering therapeutically effective amounts of inalipse, palbociclib, and fulvestrant.

[0009] In some embodiments, the patient has hormone receptor-positive, Her2-negative locally advanced or metastatic breast cancer with a PIK3CA mutation.

[0010] Also provided is a combination for treating hormone receptor-positive and HER2-negative (HR+ / HER2-) locally advanced or metastatic breast cancer, wherein the combination comprises inalipse, palbociclib, and fulvestrant.

[0011] In some embodiments, hormone receptor-positive, Her2-negative locally advanced or metastatic breast cancer is PIK3CA mutant / mutated, or has one or more PIK3CA mutations.

[0012] In some embodiments, inolic acid is administered at a daily dose of 9 mg.

[0013] In some embodiments, a method of treating a patient with PIK3CA-mutated, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer is provided, the method comprising administering a combination therapy comprising inaricetine, palbociclib, and fulvestrant to the patient, wherein the combination therapy is administered over a 28-day cycle.

[0014] In some embodiments, a method is provided for treating a patient with PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer, the method comprising administering a combination therapy to the patient, the combination therapy comprising a dosing regimen containing: a. Administer inalice during the first 28-day cycle (QD) from day 1 to day 28; b. Administer palbociclib via QD from day 1 to day 21 of the first 28-day cycle; and c. Administer fulvestrant on days 1 and 15 of the first 28-day cycle. Compared with the administration of palbociclib and fulvestrant alone to comparable patients, the combination therapy produced statistically significant and clinically meaningful improvements in patients.

[0015] In some embodiments, the method further includes one or more additional 28-day cycles, which include: a. Administer inarise on days 1 through 28 of each additional 28-day cycle; b. Administer palbociclib from day 1 to day 21 of each additional 28-day cycle; and c. Administer fulvestrant on day 1 of each additional 28-day cycle (or approximately every 4 weeks).

[0016] Also provided is a combination for treating PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer, wherein the combination comprises inaliprine, palbociclib, and fulvestrant, wherein the combination is administered over a 28-day cycle, and wherein the combination comprising inaliprine, palbociclib, and fulvestrant produces a statistically significant and clinically meaningful improvement in patients compared to administration of palbociclib and fulvestrant alone (excluding inaliprine) to comparable patients.

[0017] Also provided are combinations for treating PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer, wherein the combination is administered as a combination therapy comprising a dosing regimen containing the following: a. Administer inalice during the first 28-day cycle (QD) from day 1 to day 28; b. Administer palbociclib via QD from day 1 to day 21 of the first 28-day cycle; and c. Administer fulvestrant on days 1 and 15 of the first 28-day cycle. Furthermore, the combination of enoxacillin, palbociclib, and fulvestrant produced statistically significant and clinically meaningful improvements in patients compared to administration of palbociclib and fulvestrant alone (excluding enoxacillin) to comparable patients.

[0018] It also provides the use of inalipse in the preparation of a medicament for the treatment of PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer, wherein the treatment comprises administration in combination with a composition comprising palbociclib and fulvestrant, wherein administration of the medicament in combination with the composition comprising palbociclib and fulvestrant produces a statistically significant and clinically meaningful improvement in patients compared to administration of palbociclib and fulvestrant alone. In some embodiments, the treatment comprises administration of the medicament in combination with a composition comprising palbociclib or a pharmaceutically acceptable salt thereof and a composition comprising fulvestrant or a pharmaceutically acceptable salt thereof.

[0019] It also provides the use of the combination in the preparation of a medicine for the treatment of PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer, wherein the combination comprises inaliprine, palbociclib, and fulvestrant, wherein the combination is administered over a 28-day cycle, and wherein administration of the combination comprising inaliprine, palbociclib, and fulvestrant produces a statistically significant and clinically meaningful improvement in patients compared to administration of palbociclib and fulvestrant alone (excluding inaliprine) to comparable patients.

[0020] It is also provided that the combination is used in the preparation of a medicament for the treatment of PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer, wherein the combination is administered as a combination therapy comprising a dosing regimen containing: a. Administer inalice during the first 28-day cycle (QD) from day 1 to day 28; b. Administer palbociclib via QD from day 1 to day 21 of the first 28-day cycle; and c. Administer fulvestrant on days 1 and 15 of the first 28-day cycle. Furthermore, compared with the administration of palbociclib and fulvestrant alone (excluding inalipase) to comparable patients, the combination of inalipase, palbociclib, and fulvestrant produced statistically significant and clinically meaningful improvements in patients.

[0021] In some embodiments, the dosing regimen further includes one or more additional 28-day cycles, which include: a. Administer inarise on days 1 through 28 of each additional 28-day cycle; b. Administer palbociclib from day 1 to day 21 of each additional 28-day cycle; and c. Administer fulvestrant on day 1 of each additional 28-day cycle (or approximately every 4 weeks).

[0022] In some of these embodiments, enoxacillin is administered in doses of 3 mg, 6 mg, or 9 mg (e.g., in one or more oral tablets). In some of these embodiments, enoxacillin is administered in doses of 9 mg (e.g., in oral tablets). In some embodiments, palbociclib is administered in doses of 125 mg, for example, in oral capsules or tablets. In some embodiments, fulvestrant is administered in doses of 500 mg, for example, by intramuscular (IM) injection or infusion.

[0023] In a further aspect, a method is provided for inhibiting tumor growth or producing / increasing tumor regression in patients with PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer, the method comprising administering combination therapy to the patient according to the method detailed herein.

[0024] On the other hand, a combination is provided for use according to the purposes detailed herein, for inhibiting tumor growth or producing / increasing tumor regression in patients with PIK3CA-mutated, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer.

[0025] In another aspect, the use of, in combination with, a drug for the preparation of a medicine for inhibiting tumor growth or producing / increasing tumor regression in patients with locally advanced or metastatic breast cancer that is PIK3CA-mutated, hormone receptor-positive, and HER2-negative is provided, as detailed herein.

[0026] In some embodiments, the patient has locally advanced or metastatic breast cancer that is not suitable for curative therapy. In some embodiments, the patient has locally advanced breast cancer. In some embodiments, the patient has metastatic breast cancer. In some embodiments, the patient has locally advanced or metastatic breast cancer with a PIK3CA mutation, ER positive, PR positive, and HER2 negative. In some embodiments, the patient has no liver metastases. In some embodiments, the breast cancer is endocrine resistant. In some embodiments, the patient has disease progression during adjuvant endocrine therapy or within 12 months of completing adjuvant endocrine therapy (e.g., using an aromatase inhibitor or tamoxifen). In some embodiments, the patient has disease progression during the first two years of adjuvant endocrine therapy. In one embodiment, the adjuvant endocrine therapy is tamoxifen only. In some embodiments, the patient has disease progression during adjuvant endocrine therapy or within 12 months of completing adjuvant endocrine therapy using tamoxifen. In some embodiments, the patient has disease progression during the first two years of adjuvant endocrine therapy. In some embodiments, the patient has disease progression during the first two years of endocrine therapy using tamoxifen. In some embodiments, the patient has adequate blood and organ function within 14 days prior to the start of study treatment. In some embodiments, the patient is postmenopausal (e.g., a postmenopausal woman). In some embodiments, the patient is not postmenopausal. In some embodiments, the patient is premenopausal or perimenopausal (e.g., a premenopausal or perimenopausal woman). In some embodiments, the patient is male. In some embodiments, the patient is an adult. In some embodiments, the patient is <65 years of age. In some embodiments, the patient is an adult under 65 years of age. In some embodiments, the patient is of Asian descent. In some embodiments, the breast cancer was detected using an FDA-approved test.

[0027] Further, a method for preventing or delaying the development of resistance in tumors (e.g., breast cancer) to a therapy containing palbociclib is provided, the method comprising administering a combination therapy comprising inaliprine, palbociclib, and fulvestrant. In some embodiments, the combination therapy is administered according to any of the methods detailed herein.

[0028] Also provided is a combination for preventing or delaying the development of resistance in tumors (e.g., breast cancer) to the therapy containing palbociclib, wherein the combination comprises inalipse, palbociclib, and fulvestrant. In some embodiments, the combination is administered according to any of the uses detailed herein.

[0029] Also provided is the use of the combination in the preparation of a medicament for the prevention or delay of tumor (e.g., breast cancer) resistance to the therapy containing palbociclib, wherein said combination comprises inaliprine, palbociclib, and fulvestrant. In some embodiments, said combination is administered according to any of the uses detailed herein.

[0030] Also provided is a combination therapy comprising inaliprine, palbociclib, and fulvestrant for the treatment of adults with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced, or metastatic breast cancer, wherein the breast cancer was detected by an FDA-approved test and has recurred during or after adjuvant endocrine therapy. The following patient subgroups are also provided, which may be considered alone or in any combination to produce different patient subgroups for which the therapies described herein may be used. Subgroups are: patients who have disease progression within the first two years of adjuvant endocrine therapy (primary endocrine resistance); patients who have received adjuvant endocrine therapy with tamoxifen only; patients who are not postmenopausal; patients with PIK3CA-mutated, hormone receptor-positive, and HER2-negative metastatic breast cancer; patients with PIK3CA-mutated, estrogen receptor-positive, progesterone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer; patients who are adults; patients who are <65 years of age; and patients who are Asian adults. Attached Figure Description

[0031] Figure 1 shows the study design of INAV120.

[0032] Figure 2 shows the Kaplan-Meier plot of investigator-assessed PFS in patients identified as having a PIK3CA mutation-positive status by central FMI testing.

[0033] Figure 3 shows the Kaplan-Meier plot of OS trends in patients identified as PIK3CA mutation-positive by central FMI testing at the interim analysis.

[0034] Figure 4 shows the Kaplan-Meier plot of DOR in patients with remission who were identified as PIK3CA mutation-positive by central FMI testing.

[0035] Figure 5 shows the Kaplan-Meier plot of PFS for all patients who participated in the INAVO120 study.

[0036] Figure 6 shows a Kaplan-Meier plot of time from randomization to the end or discontinuation of next-line treatment, or death from any cause (representing PFS2).

[0037] Figure 7 shows a Kaplan-Meier plot of the time from randomization to the first subsequent chemotherapy after treatment discontinuation.

[0038] Figure 8 shows a graphical representation of the key selected AE.

[0039] Figure 9 shows a Kaplan-Meier diagram of the time to confirmed clinically significant deterioration up to the most severe level of pain.

[0040] Figure 10 shows a graphical representation of the percentage of patients based on their PRO-CTCAE scores after baseline and worst baseline.

[0041] Figure 11 shows the “trouble” that patients experience during treatment.

[0042] Figure 12 shows the Kaplan-Meier curves for progression-free survival as assessed by researchers in INAVO120.

[0043] Figure 13 shows the researcher-rated progression-free survival across the entire analysis set.

[0044] Figure 14 shows the key subgroups. The sample sizes for many groups were relatively small; therefore, the analysis was not stratified, including the analysis of “all patients”; thus, the differences in hazard ratios are relative to the stratified full analysis set.

[0045] Figure 15 shows the Kaplan-Meier curve for overall survival.

[0046] Figure 16 shows the overall response rate of the entire analysis set.

[0047] Figure 17 shows the response duration for the entire analysis set. Detailed Implementation

[0048] Definition When used in this specification and claims, the words “comprise”, “comprising”, “include”, “including”, and “includes” are intended to specify the presence of the stated features, wholes, components, or steps, but they do not exclude the presence or addition of one or more other features, wholes, components, steps, or groups thereof.

[0049] The terms “treatment” and “management” refer to therapeutic procedures and preventative or preventative measures aimed at preventing or mitigating (alleviating) undesirable physiological changes or conditions, such as the growth, development, or spread of cancer. For the purposes of this invention, beneficial or desired clinical outcomes include, but are not limited to, detectable or undetectable symptom relief, reduction in disease severity, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or alleviation of the disease state, and remission (whether partial or complete). “Treatment” may also mean prolonged survival compared to expected survival without treatment. Individuals requiring treatment include those already suffering from the condition or disease, those susceptible to the condition or disease, and those with the condition or disease to be prevented.

[0050] The phrase "therapeuticly effective amount" refers to the amount of the compound of the present invention used to: (i) treat a specific disease, symptom, or disorder; (ii) reduce, improve, or eliminate one or more symptoms of a specific disease, symptom, or disorder; or (iii) prevent or delay the onset of one or more symptoms of a specific disease, symptom, or disorder described herein. In the case of cancer, a therapeutically effective amount of the drug can reduce the number of cancer cells; reduce the size of the tumor; inhibit (i.e., to a certain extent slow down and preferably stop) the infiltration of cancer cells into surrounding organs; inhibit (i.e. ， (To some extent, it slows down and preferably stops) tumor metastasis; to some extent, it inhibits tumor growth; and / or to some extent, it relieves one or more symptoms associated with cancer. To some extent, the drug can stop growth and / or kill existing cancer cells; it can inhibit cell growth and / or have cytotoxicity. For cancer therapies, efficacy can be measured, for example, by assessing time to progression (TTP) and / or determining response rate (RR).

[0051] "Time to Progression" or "TTP" refers to the time from randomization to objective tumor progression.

[0052] The "objective response rate" or "ORR" refers to the proportion of patients who achieve a confirmed complete or partial response within two consecutive periods of ≥ 4 weeks, as determined by investigators according to RECIST v1.1.

[0053] "Best Overall Response Rate" or "BOR" refers to the proportion of patients who achieve CR or PR as determined by investigators according to RECIST v1.1.

[0054] "Duration of Response" or "DOR" refers to the time from the first recorded objective response to disease progression or death from any cause (whichever comes first), as determined by the investigator according to RECIST v1.1.

[0055] "Clinical benefit rate" or "CBR" refers to the proportion of patients whose disease has been stable for at least 24 weeks or who have a confirmed complete or partial response, as determined by investigators according to RECIST v1.1.

[0056] "Overall survival" or "OS" refers to the time from enrollment to death from any cause.

[0057] "Time to Pain Worsening (TTD)" refers to the time from randomization to the first recording of the "most severe pain" item on the Brief Pain Scale (BPI-SF) with an increase of ≥ 2 points from baseline.

[0058] "Time to decline in physical function (TTD)" refers to the time from randomization to the first recorded decline of ≥ 10 points from baseline in the physical function scale (items 1-5) of the European Organization for Research in Cancer Treatment of Life Quality-Scale 30 (EORTC QLQ-C30).

[0059] "Time to role function deterioration (TTD)" refers to the time from randomization to the first recording of a ≥ 10-point decrease in the EORTC QLQ-C30 Role Function Scale (items 6 and 7) from baseline.

[0060] "Time to deterioration of general health status (GHS) / health-related quality of life (HRQoL) (TTD)" refers to the time from randomization to the first recording of the EORTC QLQ-30 GHS / HRQoL scale (items 29 and 30) with a decrease of ≥ 10 points from baseline.

[0061] "Progression-free survival" or "PFS" refers to the time from enrollment to the date of first recorded disease progression or death from any cause (whichever comes first), as determined by the investigator according to RECIST v1.1.

[0062] "Complete response" or "CR" refers to the disappearance of all target and non-target lesions and (if applicable) the normalization of tumor marker levels.

[0063] "Partial response," "PR," or "non-CR / non-PrD" refers to the persistence of one or more non-target lesions and / or (if applicable) tumor marker levels remaining above normal limits. PR can also refer to a ≥30% reduction in the sum of the diameters of target lesions, the appearance of new lesions in the absence of CR, and clear progression of non-target lesions.

[0064] "Progressive disease" or "PrD" refers to an increase of ≥ 20% in the sum of the diameters of target lesions, clear progression of non-target lesions, and / or the appearance of new lesions.

[0065] "Stable disease" or "SD" refers to a condition that has neither shrunk sufficiently to achieve CR or PR nor grown sufficiently to achieve PrD.

[0066] "Application period" or "cycle" refers to a period of time including the application of one or more of the pharmaceutical agents described herein, and optionally a period of time excluding the application of one or more of the pharmaceutical agents described herein. For example, the total length of a cycle may be 28 days, including a 21-day application of one or more pharmaceutical agents and a 7-day rest period. "Rest period" refers to a period of time during which at least one of the pharmaceutical agents described herein is not applied. In one embodiment, a rest period refers to a period of time during which no pharmaceutical agent described herein is applied.

[0067] "Dosing regimen" refers to the period of administration of the drug described herein, which includes one or more cycles, wherein each cycle may include administration of the drug described herein at different times and in different amounts.

[0068] "Once a day" (QD) means applying the compound once a day.

[0069] Graded adverse events refer to the severity level determined by NCI CTCAE. In one embodiment, adverse events are graded according to the table below.

[0070] The term "detection" includes any detection method, including direct and indirect detection.

[0071] The term “prognosis” is used in this article to refer to the prediction of the likelihood of death or progression attributable to cancer, including recurrence, metastasis, and drug resistance in neoplastic diseases such as cancer.

[0072] The term "prediction" (and variations such as "expectation") is used herein to refer to the likelihood that a patient will produce a favorable or unfavorable response to a drug or a group of drugs. In one embodiment, prediction involves the extent of those responses. In another embodiment, prediction involves whether a patient will survive and / or the probability of survival after treatment, for example, treatment with a specific therapeutic agent and / or surgical resection of the primary tumor and / or chemotherapy for a period of time without cancer recurrence. By selecting the most appropriate treatment modality for any particular patient, the predictive method of the present invention can be clinically used to make treatment decisions. The predictive method of the present invention is a valuable tool for predicting whether a patient is likely to respond favorably to a treatment regimen (such as a given treatment regimen) or whether the patient is likely to follow the treatment regimen for long-term survival, including, for example, the administration of a given therapeutic agent or combination, surgical intervention, chemotherapy, etc.

[0073] When used according to the invention, the term “increased resistance” to a particular therapeutic agent or treatment option refers to a reduced response to a standard dose of the drug or to a standard treatment regimen.

[0074] A “response” may be assessed using any endpoint that indicates benefit to the patient, including but not limited to: (1) inhibition of tumor growth to some extent, including slowing or stopping growth completely; (2) reduction of the number of tumor cells; (3) reduction of tumor size; (4) inhibition (e.g., reduction, slowing or stopping) of tumor cell infiltration into adjacent organs and / or tissues; (5) inhibition (e.g., reduction, slowing or stopping) of metastasis; (6) enhancement of the antitumor immune response, which may, but does not necessarily, lead to tumor regression or rejection; (7) some degree of relief of one or more tumor-related symptoms; (8) increased survival time after treatment; and / or (9) a decrease in mortality at a given time point after treatment.

[0075] "Biomarker" is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathological processes, or pharmacological responses to therapeutic interventions. Biomarkers can be of several types: predictive, prognostic, or pharmacodynamic (PD). Predictive biomarkers predict which patients are likely to respond to or benefit from a particular therapy. Prognostic biomarkers predict a patient's likely disease course and can guide treatment. Pharmacodynamic biomarkers confirm drug activity and can optimize dosage and administration schedules.

[0076] By analyzing biological samples using one or more methods commonly used in establishing pharmacodynamics (PD), the “alteration” or “regulation” of the state of biomarkers occurring in vitro or in vivo is detected, including PIK3CA mutations or a set of PIK3CA mutations. One or more methods commonly used in establishing pharmacodynamics include: (1) sequencing the genomic DNA or reverse transcription PCR product of the biological sample to detect one or more mutations; (2) assessing gene expression levels by quantitative information levels or evaluating copy numbers; and (3) analyzing proteins by immunohistochemistry (IHC), immunocytochemistry, ELISA, or mass spectrometry to detect protein degradation, stabilization, or post-translational modifications (such as phosphorylation or ubiquitination).

[0077] "Chemotherapy agents" are biological (macromolecule) or chemical (small molecule) compounds that can be used to treat cancer, regardless of their mechanism of action.

[0078] The term "instructions for use" is used to refer to the instructions that are typically included in the commercial packaging of a therapeutic product, which contain information concerning the indications, usage, dosage, administration, contraindications and / or warnings related to the use of such therapeutic products.

[0079] As used herein, the phrase "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of the compounds of this invention. Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucurons, saccharates, formates, benzoates, glutamates, mesylates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and dihydroxynaphthyl salts (i.e., 1,1'-methylene-di-(2-hydroxy-3-naphthylcarbamate)). Pharmaceutically acceptable salts may involve inclusion complexes of another molecule, such as acetate ions, succinate ions, or other counterions. Counterions can be either organic or inorganic components that stabilize the charge on the parent compound. Furthermore, pharmaceutically acceptable salts can have more than one charged atom in their structure. Examples where multiple charged atoms are part of a pharmaceutically acceptable salt can have multiple counterions. Therefore, pharmaceutically acceptable salts can have one or more charged atoms and / or one or more counterions.

[0080] The desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art. For example, the free base can be treated with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc., or with organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranotropic acids (such as glucuronic acid or galacturonic acid), α-hydroxy acids (such as citric acid or tartaric acid), amino acids (such as aspartic acid or glutamic acid), aromatic acids (such as benzoic acid or cinnamic acid), sulfonic acids (such as p-toluenesulfonic acid or ethanesulfonic acid), etc. Acids generally considered suitable for the formation of pharmaceutically useful or acceptable salts from basic pharmaceutical compounds are discussed in the following literature, such as P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1 19; P. Gould, International Journal of Pharmaceutics (1986) 33 201 217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; Remington's Pharmaceutical Sciences, 18th edition, (1995) Mack Publishing Co., Easton, PA; and The Orange Book (Food & Drug Administration, Washington, D.C. on its official website). These publications are incorporated herein by reference.

[0081] The phrase “pharmaceutically acceptable” means that the substance or composition must be chemically and / or toxicologically compatible with other ingredients in the formulation and / or with the patients treated with it.

[0082] As used herein, the term "synergistic" refers to a therapeutic combination that is more effective than the additive effect of two or more single agents. The determination of synergistic interactions between compounds of inalipse or their pharmaceutically acceptable salts and one or more chemotherapeutic agents can be based on results obtained from the assays described herein. The results of these assays can be analyzed using the Chou and Talalay combination method and dose-response analysis using CalcuSyn® software to obtain the combination index (Chou and Talalay 1984, Adv. Enzyme Regul 22:27-55). The combinations provided by this invention have been evaluated in several assay systems and the data can be analyzed using a standard procedure described by Chou and Talalay in Chapter 2 of "New Avenues in Developmental Cancer Chemotherapy," Academic Press, 1987, for quantifying synergistic, additive, and antagonistic effects in anticancer agents. A combination index value less than 0.8 indicates synergy, a value greater than 1.2 indicates antagonism, and a value between 0.8 and 1.2 indicates additive effects. Combination therapies can provide "synergistic" effects and are demonstrated to be "synergistic," meaning that the effect achieved when the active ingredients are used together is greater than the sum of the effects produced by using the compounds alone. Synergistic effects can be obtained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined unit dosage form; (2) delivered alternately or as separate formulations in parallel; or (3) through some other protocol. When using alternating therapy, synergistic effects can be achieved if compounds are administered or delivered sequentially, for example, by injection in separate syringes or as separate pills or tablets. Generally, in alternating therapy, the order is the sequential administration of each active ingredient at an effective dose, while in combination therapy, two or more active ingredients at effective doses are administered together. Combination effects were assessed using the BLISS independence model and the highest single-drug (HSA) model (Lehár et al. 2007, Molecular Systems Biology 3:80). The BLISS score quantifies the enhancement of single-drug responses, with a BLISS score >0 indicating a greater than simple summation. An HSA score >0 indicates that the combination effect is greater than the maximum single-drug response at the corresponding concentration.

[0083] Clinical compound Inalice: Enallix is ​​an oral therapy with high in vitro potency and selectivity for PI3Kα inhibition and the ability to specifically trigger the degradation of mutant PI3Kα protein. Enallix is ​​designed to help minimize overall therapeutic toxicity and, unlike other PI3K inhibitors, possesses high in vitro potency and specificity for the inhibition of the PI3Kα (PI3Kα) subtype, along with its unique mechanism of action leading to the specific degradation of mutant PI3Kα. See also Juric et al. A phase I / Ib study of inavolisib (GDC-0077) in combination with fulvestrant in patients (pts) with PIK3CA-mutated hormone receptor-positive / HER2-negative (HR+ / HER2–) metastatic breast cancer. Presented at San Antonio Breast Cancer Symposium, December 7–10, 2020; San Antonio, USA. Abstract#P5-17-05; and Hong R. et al. GDC-0077 is a selective PI3K alpha inhibitor that demonstrates robust efficacy in PIK3CA mutant breast cancer models as a single agent and in combination with standard of care therapies. Cancer Res. 2018;78(4):4-1. With this unique dual mechanism of action, inavolisib provides well-tolerated, durable disease control and may improve outcomes in patients with HR-positive / HER2-negative, PIK3CA-mutated advanced breast cancer. Mutations in PIK3CA can lead to mutated PI3Kα protein, which can cause uncontrolled tumor growth, disease progression, and resistance to endocrine-based therapies.

[0084] Inalice, CAS Registry No. 2060571-02-8, Genentech, US 9650393; named ( S )-2-((2-(( S )-4-(difluoromethyl)-2-oxooxazolidine-3-yl)-5,6-dihydrobenzo[f Imidazolidine[1,2-] d [1,4]oxazine-9-yl)amino)propionamide has the following structure: .

[0085] Inarise is also known as inavolisib, RG6114, RO7113755, or by its chemical name (2S)-2-[[2-[(4S)-4-(difluoromethyl)-2-oxo-3-oxazolidinyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazolidin-9-yl]amino]propionamide.

[0086] Enallix exerts its activity by binding to the ATP-binding site of PI3K, thereby inhibiting the phosphorylation of membrane-bound 4,5-phosphatidylinositol diphosphate (PIP2) to 3,4,5-phosphatidylinositol triphosphate (PIP3). Inhibition of PIP2 phosphorylation to PIP3 reduces downstream activation of AKT and pS6, leading to decreased cell proliferation, metabolism, and angiogenesis. Non-clinical studies have shown that enallix specifically degrades mutant p110α, inhibiting… PIK3CA Proliferation of mutant breast cancer cell lines and induction of apoptosis, inhibiting the proliferation of cells carrying mutant breast cancer cells. PIK3CA The mutation inhibits tumor growth in a human breast cancer xenograft model and reduces downstream PI3K pathway markers, including pAKT (phosphorylated form of AKT), pPRAS40, and pS6.

[0087] Palbociclib: Palbociclib is a selective inhibitor of cyclin-dependent kinases CDK4 and CDK6 (Finn et al. (2009)). Breast cancer research: BCR 11 (5):R77; Rocca et al. (2014) Expert Opin Pharmacothe r 15 (3):407–20; US 6936612; US 7863278; US 7208489; US 7456168; USRE47739; US10723730). Palbociclib can be prepared and characterized as described in US 7345171. IBRANCE® is approved for the treatment of breast cancer.

[0088] Palbociclib (PD-0332991, IBRANCE®, Pfizer, Inc., CAS Registry No. 571190-30-2), named 6-acetyl-8-cyclopentyl-5-methyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one, has the following structure: Palbociclib is a CDK4 / 6 inhibitor, and when combined with letrozole or fulvestrant, it is an effective treatment for postmenopausal HR+ (positive) / HER2- (negative) breast cancer patients. The main toxicity of palbociclib when combined with letrozole or fulvestrant is neutropenia (Finn et al. (2015)). Lancet Oncol 16:25-35; Turner et al. (2015) N Engl J Med 373:209-19). When combined with letrozole, 36% of patients required a dose reduction of ≥1 dose of palbociclib; dose maintenance and cycle delays were reported in 70% and 68% of patients, respectively (Finn et al. (2016)). J Clin Oncol 34 (suppl; abstr 507)). When combined with fulvestrant, 34% of patients required a dose reduction of ≥1 dose of palbociclib; dose maintenance and cycle delays were reported in 54% and 36% of patients, respectively (Cristofanilli et al. (2016)). Lancet Oncol 17:425-39). Myelosuppression is a potential toxicity of inalice.

[0089] Fulvestrant: Fulvestrant is an ER antagonist and a relatively well-tolerated and effective treatment for postmenopausal HR+ breast cancer patients. The expected toxicities of enoxaparin and fulvestrant do not overlap.

[0090] Fulvestrant (FASLODEX®, AstraZeneca, CAS Registry No. 129453-61-8) is approved by the FDA for the treatment of hormone receptor-positive (HR+) metastatic breast cancer in postmenopausal women whose disease has progressed after anti-estrogen therapy (Kansra (2005)). Mol Cell Endocrinol 239(1-2):27–36; Flemming et al. (2009) Breast Cancer Res Treat May; 115(2):255-68; Valachis et al. (2010) Crit Rev Oncol HematolMarch; 73(3):220-7). Fulvestrant is a non-agonist estrogen receptor (ER) antagonist that works by downregulating and degrading estrogen receptors (Croxtall (2011)). Drugs 71(3):363–380). Fulvestrant is also a selective estrogen receptor downregulator (SERD).

[0091] The fulvestrant is named (7α,17β)-7-{9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl}estradiol-1,3,5(10)-trien-3,17-diol and has the following structure: Fulvestrant belongs to the class of reversible steroidal ER antagonists that directly compete with estrogen for ER binding and lacks the partial agonist properties of tamoxifen. Upon binding to the ER, it blocks estrogen signaling and increases ER protein degradation. Fulvestrant has approximately 100 times the affinity for the ER compared to tamoxifen (Howell et al. (2000) Cancer 89:817-25). Fulvestrant (250 mg once monthly) was approved by the FDA in 2002 and by the EMA in 2004 for the treatment of HR-positive mycobacterial cystic breast cancer (MBC) in postmenopausal women whose disease has progressed following anti-estrogen therapy. In a multicenter phase III study, fulvestrant was found to be at least equivalent to anastrozole (a nonsteroidal anti-inflammatory drug) in a second-line setting (Howell et al. (2002)). J Clin Oncol 20:3396-3403; Osborne CK et al. (2002) J Clin Oncol 20:3386-95). For first-line treatment of advanced breast cancer, fulvestrant is as effective as tamoxifen (Howell et al. (2004) J Clin Oncol 22:1605-1613), and shows similar activity to the nonsteroidal AI exemestane in patients with post-AI metastatic disease background (Chia et al. (2008)). J Clin Oncol 26:1664-1670). High-dose fulvestrant (500 mg once monthly) has been shown to be at least as effective as anastrozole in terms of clinical benefit rate (CBR) and overall response rate, and is associated with significantly longer time to progression in women with advanced HR-positive breast cancer treated as first-line therapy (Robertson et al. (2009)). J Clin Oncol27:4530-4535). High-dose fulvestrant has recently been shown to provide superior progression-free survival (PFS) in women with ER-positive advanced breast cancer treated with 500 mg compared to those treated with 250 mg (Di Leo et al. (2010)). J Clin Oncol 28:4594-4600). Fulvestrant (250 mg and 500 mg) was well tolerated in these studies and produced less estrogenic effects than tamoxifen and caused less arthralgia than the AI ​​anastrozole (Osborne et al. (2002)). J Clin Oncol (20:3386-3395). These results led to the approval of 500 mg fulvestrant once monthly as the currently approved recommended dose in the US and EU (2010) for postmenopausal women whose disease has spread after AI treatment. These studies demonstrate that fulvestrant is an important treatment option for patients with advanced breast cancer and are therefore considered an appropriate control therapy for this study.

[0092] Combination therapy On the one hand, a combination or combination therapy comprising inaliprine, palbociclib, and fulvestrant is provided that produces statistically significant and clinically meaningful improvement in patients with PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer compared with palbociclib and fulvestrant alone (excluding inaliprine).

[0093] Compared to palbociclib and fulvestrant alone in similar patients, the combination of enoxaparin with palbociclib and fulvestrant (as first-line treatment) more than doubled progression-free survival in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative, endocrine-resistant locally advanced or metastatic breast cancer. The enoxaparin combination has the potential to address treatment resistance and poor prognosis associated with PIK3CA mutations.

[0094] The combination or combination therapies described herein may be provided in the form of a kit comprising one or more of the agents for administration. In one embodiment, the kit comprises enoxacillin and fulvestrant. In another embodiment, the kit comprises enoxacillin, palbociclib, and fulvestrant. In one embodiment, the agents of the combination or combination therapies described herein are provided in the form of an easy-to-administer or, for example, reconstituted kit. The kits described herein may include instructions for use, such as package inserts. In one embodiment, the instructions for use are package inserts, with one package insert provided for each agent in the kit.

[0095] Furthermore, a kit is provided for carrying out the methods detailed herein, which contains the pharmaceutical composition or combination therapy detailed herein and instructions for use in the treatment of breast cancer.

[0096] The kit generally includes suitable packaging. The kit may include one or more containers containing any of the pharmaceutical compositions described herein. Each component (if there is more than one component) may be packaged in a separate container, or, where cross-reactivity and shelf life permit, some components may be combined in one container. One or more components of the kit may be sterile and / or may be packaged in sterile containers.

[0097] Method This article provides a method for treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer. In one embodiment, the method includes treating patients with PIK3CA-mutated, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer by administering a combination therapy comprising enoxaparin, palbociclib, and fulvestrant, which produces a statistically significant and clinically meaningful improvement in patients compared to administering palbociclib and fulvestrant alone (excluding enoxaparin) to comparable patients.

[0098] It also provides a method for treating patients with hormone receptor-positive and HER2-negative (HR+ / HER2-) locally advanced or metastatic breast cancer, which includes administering a therapeutically effective amount of inalipse or a pharmaceutically acceptable salt thereof, palbociclib, and fulvestrant.

[0099] PIK3CA mutations are found in approximately 40% of HR-positive breast cancers and are associated with tumor growth, disease progression, and treatment resistance. In one aspect, a method is provided for treating patients with PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer, comprising administering a combination therapy including enoxaparin, palbociclib, and fulvestrant, wherein the combination therapy including enoxaparin, palbociclib, and fulvestrant produces a statistically significant and clinically meaningful improvement compared to comparable patients treated with palbociclib and fulvestrant alone (excluding enoxaparin). In some embodiments, the median progression-free survival (PFS) of patients treated with the combination therapy including enoxaparin, palbociclib, and fulvestrant is approximately 5 to 12 months longer than the median PFS of patients treated with palbociclib and fulvestrant alone (excluding enoxaparin). That isThe difference (ΔPFS) between the median progression-free survival (PFS) in patients treated with combination therapy comprising inaliprine, palbociclib, and fulvestrant and the median PFS in comparable patients treated with palbociclib and fulvestrant alone is approximately 5 to 10 months (e.g., 5, 6, 7, 8, 9, 10, 11, or 12 months). In some embodiments, ΔPFS is 6, 7, 8, 9, 10, or 11 months. In some embodiments, ΔPFS is 6–7 months, 7–8 months, 8–9 months, or 9–10 months. In some embodiments, the p-value is less than 0.0001 (<0.0001) and the hazard ratio (HR) is less than 0.69. In some embodiments, the HR is between 0.6 and 0.69, between 0.5 and 0.59, between 0.4 and 0.49, or between 0.3 and 0.39. In some embodiments, the objective response rate (ORR) in patients treated with combination therapy comprising inaliprine, palbociclib, and fulvestrant is about 10% to 50% higher (e.g., 20% to 40% or 25% to 35% higher) than in comparable patients treated with palbociclib and fulvestrant alone. In some embodiments, the clinical benefit rate (CBR) in patients treated with combination therapy comprising inaliprine, palbociclib, and fulvestrant is about 10% to 50% higher (e.g., 20% to 40% or 25% to 35% higher) than in comparable patients treated with palbociclib and fulvestrant alone.

[0100] Compared to treatment with palbociclib and fulvestrant alone in comparable patient subgroups, the clinical benefit of combination therapy comprising inaliprine, palbociclib, and fulvestrant may be greater or less in some patient subgroups. See Table A1 (including 270 patients whose PIK3CA mutation positivity was identified by central testing using the F1LCDx assay) and Figure 14 (including all 325 patients in the INAVO120 study). For example, patients without visceral disease had a more significant increase in PFS (ΔPFS approximately 17–18 months) when treated with inaliprine in combination compared to treatment with palbociclib and fulvestrant alone. Patients in this study had received prior adjuvant or neoadjuvant endocrine therapy (e.g., tamoxifen and aromatase inhibitors). Patients who had previously received tamoxifen alone benefited more from the enalixe combination (compared to palbociclib and fulvestrant alone) than those who had previously received aromatase inhibitors (ΔPFS of approximately 5 months) (ΔPFS of approximately 14 months). Patients who were not postmenopausal at randomization had a larger ΔPFS (approximately 14 months) than those who were postmenopausal at randomization (ΔPFS of approximately 6 months). Hormone receptor status also affected benefit. ΔPFS was approximately 11–13 months in ER-positive and PR-positive patients, while it was approximately 5 months in ER-positive and PR-negative patients. The majority of patients in the INAVO120 study (266 of 325) were <65 years old. A relatively small number of patients aged ≥65 years appeared to perform poorly in the enalixe group; while patients younger than 65 years performed better (ΔPFS of approximately 9 months).

[0101] In some embodiments of the methods detailed herein for treating PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer in patients, the patients received prior adjuvant or neoadjuvant endocrine therapy with tamoxifen alone. In some embodiments, the patients received prior adjuvant or neoadjuvant endocrine therapy consisting solely of an aromatase inhibitor or an inhibitor comprising or containing an aromatase inhibitor. In some embodiments, the patients have no visceral disease (according to the electronic case report form (eCRF)). In some embodiments, the patients have visceral disease (according to the eCRF). In some embodiments, the patients are not postmenopausal. In some embodiments, the patients are postmenopausal.

[0102] In some embodiments, the patient has not received prior therapy for LA / mBC. In some embodiments, the patient has a fasting blood glucose level <126 mg / dL. In some embodiments, the patient has HbA1c <6.0%. 1CIn some embodiments, the patient has a fasting blood glucose level <126 mg / dL and HbA1c <6.0%. 1C .

[0103] In some embodiments, a method is provided for treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer in a patient with one or more PIK3CA mutations, the method comprising administering to the patient a combination therapy comprising enoxacin, palbociclib, and fulvestrant, wherein the combination therapy is administered over a 28-day cycle and comprises enoxacin, palbociclib, and fulvestrant, which produces a statistically significant and clinically meaningful improvement in the patient compared to administering palbociclib and fulvestrant alone to comparable patients.

[0104] In some embodiments, a method is provided for treating a patient with PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer, the method comprising administering a combination therapy to the patient, the combination therapy comprising a dosing regimen containing: a. Administer inalice during the first 28-day cycle (QD) from day 1 to day 28; b. Administer palbociclib via QD from day 1 to day 21 of the first 28-day cycle; and c. Administer fulvestrant on days 1 and 15 of the first 28-day cycle. Compared with the administration of palbociclib and fulvestrant alone to comparable patients, the combination therapy consisting of inalipase, palbociclib, and fulvestrant produced statistically significant and clinically meaningful improvements in patients.

[0105] In some embodiments, the method further includes one or more additional 28-day cycles, which include: a. Administer inarise on days 1 through 28 of each additional 28-day cycle; b. Administer palbociclib from day 1 to day 21 of each additional 28-day cycle; and c. Administer fulvestrant on day 1 of each additional 28-day cycle (or approximately every 4 weeks).

[0106] In some embodiments, the patient has hormone receptor-positive, Her2-negative locally advanced or metastatic breast cancer with a PIK3CA mutation. In some embodiments, the patient has a PIK3CA mutation at one or more of positions 88, 106, 111, 118, 345, 420, 453, 542, 545, 546, 1043, 1047, and 1049. In some embodiments, the patient has a PIK3CA mutation at one or more of positions H1047, E545, E542, Q546, N345, C420, M1043, G1049, E453, K111, G106, G118, and R88. In some embodiments, the patient has a mutated PIK3CA containing one or more mutations selected from the group consisting of: 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, and R88Q. In some embodiments, the patient has a mutated PIK3CA containing one or more mutations selected from the group consisting of: E542K, E545K, Q546R, H1047L, and H1047R. In some embodiments, the patient has breast cancer expressing a PIK3CA mutation selected from the group consisting of: 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, and R88Q. In some embodiments, the patient has breast cancer expressing a PIK3CA mutation selected from the group consisting of E542K, E545K, Q546R, H1047L, and H1047R. In some embodiments, the patient has a mutated PIK3CA containing one mutation selected from the group consisting of E542K, E545K, Q546R, H1047L, and H1047R, and a second mutation (e.g., a second mutation selected from E453Q / K, E726K, and M1043L / I).In some embodiments, the patient has breast cancer expressing a PIK3CA mutation, which expresses two mutations selected from the group consisting of: E542K + E453Q / K, E542K + E726K, E542K + M1043L / I; E545K + E453Q / K, E545K + E726K, E545K + M1043L / I; H1047R + E453Q / K and H1047R + E726K.

[0107] PIK3CA The mutated tumor status can be assessed by central testing of blood (e.g., ctDNA) or in-hospital testing of blood (e.g., ctDNA) or tumor tissue. In some embodiments, the identification of eligible tumors is... PIK3CA The central testing for mutations is performed in FoundationOne fluid clinical trials conducted by Foundation Medicine, Inc. In some embodiments, in-hospital testing of blood or tumor tissue is performed in a CLIA-certified or equivalent laboratory using a sponsor-approved PCR- or NGS-based assay.

[0108] In one embodiment, the method includes a combination therapy comprising: (i) enoxaparin; (ii) fulvestrant; and (iii) palbociclib. In another embodiment, the method includes a combination therapy administered according to the dosing regimen described herein, comprising: (i) enoxaparin; (ii) palbociclib; and (iii) fulvestrant.

[0109] In a further aspect, a method is provided for inhibiting tumor growth or producing / increasing tumor regression in patients with PIK3CA-mutated / mutated, hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, the method comprising administering combination therapy to the patient according to the method detailed herein.

[0110] In some embodiments, estrogen receptor (ER) positive and / or progesterone receptor (PR) positive tumors are documented according to the American Society of Clinical Oncology / American Society of Pathologists (ASCO / CAP) guidelines and are defined as tumor cells with ≥ 1% positive staining based on the most recent tumor biopsy and in-hospital assessment.

[0111] Hormone receptor-positive (HR+) breast cancer cells possess estrogen receptors (ER) or progesterone receptors (PR), or both. In some embodiments of the methods detailed herein, HR-positive breast cancer is ER-positive. In some embodiments, HR-positive breast cancer is PR-positive. In some embodiments, HR-positive breast cancer is both ER-positive and PR-positive. In some embodiments, HR-positive breast cancer is both ER-positive and PR-negative.

[0112] In some embodiments, HER2-negative tumors are documented according to the ASCO / CAP guidelines and defined as HER2 immunohistochemistry (IHC) scores of 0 or 1+, or IHC scores of 2+ accompanied by negative fluorescence, chromogenic or silver staining. In situ Hybridization tests showed that there was no HER2 Gene amplification, or a HER2 / CEP17 ratio <2.0 based on recent tumor biopsy and in-hospital assessment.

[0113] In some embodiments, the patient is a woman or man aged 18 years or older.

[0114] In some embodiments, the patient is an adult under the age of 65.

[0115] In some embodiments, the patient is postmenopausal (e.g., a postmenopausal woman). A postmenopausal woman is defined as having at least one of the following criteria: (1) age ≥ 60 years; (2) age < 60 years and 12 months of amenorrhea without oral contraceptives, hormone replacement therapy, or gonadotropin-releasing hormone agonists or antagonists, with follicle-stimulating hormone and plasma estradiol levels within the postmenopausal range as assessed by an in-hospital laboratory; (3) a history of bilateral oophorectomy (≥ 14 days prior to the first treatment on day 1 of cycle 1 and back to baseline).

[0116] In some embodiments, the patient is a premenopausal or perimenopausal woman (i.e., . (Those who do not meet the postmenopausal criteria) and have started luteinizing hormone-releasing hormone (LHRH) agonist therapy (e.g., goserelin or leuprorelin) at least 2 weeks before day 1 of cycle 1 and continue during the study treatment.

[0117] In some embodiments, the patient is male and has started treatment with an LHRH agonist (e.g., goserelin or leuprorelin) at least 2 weeks prior to day 1 of cycle 1 and continues during the study treatment.

[0118] The pharmaceutical agent described herein may be administered according to the packaging insert. In one embodiment of the methods described herein, the pharmaceutical agent may be administered in an effective amount as described herein. In some embodiments, palbociclib or fulvestrant (where applicable) may be administered at their approved dose via the approved route of administration.

[0119] The agents in the combination therapies detailed herein can be administered simultaneously or sequentially. Two agents in a triple therapy combination may be administered simultaneously, while the third agent may be administered before or after. For example, in one embodiment of the method described herein, the administration of enoxaparin occurs before the administration of another agent (e.g., fulvestrant). In one embodiment of the method described herein, the administration of enoxaparin occurs before the administration of fulvestrant, and the administration of fulvestrant occurs before the administration of palbociclib. In another embodiment, enoxaparin is administered before or simultaneously with palbociclib, and fulvestrant is subsequently administered.

[0120] In some embodiments, enoxacillin is administered in doses of 3 mg, 6 mg, or 9 mg (e.g., in one or more oral tablets). In some embodiments, enoxacillin is administered orally at a daily dose of 9 mg. In some of these embodiments, enoxacillin is administered in doses of 9 mg (e.g., in oral tablets).

[0121] In one embodiment of the methods described herein, palbociclib is administered as an agent in the triple combination therapy described herein. In one embodiment, palbociclib is administered orally at a dose of 125 mg, 100 mg, or 75 mg. In another embodiment, palbociclib is administered orally at a dose of 125 mg. In another embodiment, palbociclib is administered orally at a dose of 100 mg. In yet another embodiment, palbociclib is administered orally at a dose of 75 mg. In such embodiments, palbociclib is administered via QD from day 1 to day 21 of each 28-day cycle. In another embodiment of the methods described herein, palbociclib is administered according to the package insert. In one embodiment, palbociclib is administered orally via QD from day 1 to day 21 of each 28-day cycle at the dose described herein. In yet another embodiment, the dose of palbociclib is changed from the initial dose (e.g., reduced). In one such embodiment, the dose of palbociclib administered is reduced from 125 mg to 100 mg and in one embodiment may be further reduced to 75 mg. In another embodiment, palbociclib is administered using the dosing regimen described herein.

[0122] In some embodiments, palbociclib is administered in a dose of 125 mg, for example, as an oral capsule or tablet.

[0123] In another embodiment of the method described herein, fulvestrant is administered at a dose of approximately 500 mg. In another embodiment of the method described herein, fulvestrant is administered according to the packaging insert. In one embodiment, fulvestrant is administered as two separate intramuscular injections of 250 mg. In another embodiment, fulvestrant is administered according to the dosing regimen described herein. In one such embodiment, fulvestrant is administered on days 1 and 15 of the first 28-day cycle and on day 1 of each subsequent 28-day cycle thereafter.

[0124] In some embodiments, fulvestrant is administered in a dose of 500 mg, for example, via intramuscular (IM) infusion.

[0125] In one embodiment, the method described herein includes administering the combination therapy described herein according to a dosing regimen comprising one 28-day cycle. In another embodiment, the method described herein includes administering the combination therapy described herein according to a dosing regimen comprising a first 28-day cycle followed by another 28-day cycle. In yet another embodiment, the method described herein includes administering the combination therapy described herein according to a dosing regimen comprising a first 28-day cycle followed by 2-10 28-day cycles. In still another embodiment, the method described herein includes administering the combination therapy described herein according to a dosing regimen comprising a first 28-day cycle followed by 2-8 28-day cycles. In one embodiment of the method described herein, the dosing regimen comprises a first 28-day cycle, followed by 2-36, 2-30, 2-24, 2-18, 2-12, 2-10, 2-8, 2-6, or 2-4 28-day cycles.

[0126] This article provides further examples of methods for treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer.

[0127] In one embodiment, the efficacy of the combination therapy is measured as a function of progression-free survival (PFS). In one such embodiment, patients experienced an increase in PFS of 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or more months compared to no treatment or SOC treatment. In one embodiment, PFS was measured at least 64 months after the first dose of the combination therapy described herein. In another embodiment, efficacy is measured as a function of PFS in a biomarker-positive patient group (e.g., the biomarker group described herein, including PIK3CA) compared to a biomarker-negative patient group.

[0128] In one embodiment, treatment with combination therapy according to the methods provided herein increases the patient's overall survival (OS) by 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or more months compared to no treatment or SOC treatment. In one embodiment, treatment with combination therapy according to the methods provided herein increases the patient's objective response rate (ORR). In another embodiment, the efficacy of the response is measured as a function of the dose-or-response ratio (DOR) compared to no treatment or SOC treatment. In yet another embodiment, the efficacy of the response is measured as a function of the critical benefit rate (CBR) compared to no treatment or SOC treatment.

[0129] In another embodiment, the patient's TTP increased after treatment with combination therapy according to the methods provided herein. In another embodiment, the patient's PFS increased after treatment with combination therapy according to the methods provided herein. In one embodiment provided herein, the patient was diagnosed with CR after treatment with combination therapy according to the methods provided herein. In one embodiment provided herein, the patient was diagnosed with PR after treatment with combination therapy according to the methods provided herein. In one embodiment provided herein, the patient was diagnosed with SD after treatment with combination therapy according to the methods provided herein.

[0130] In some embodiments, the patient has locally advanced or metastatic breast cancer (e.g., determined by histology or cytology) that is not suitable for curative treatments (e.g., surgery or radiation therapy with curative purposes).

[0131] In some embodiments, the patient experiences disease progression during adjuvant endocrine therapy or within 12 months of completing adjuvant endocrine therapy (e.g., with an aromatase inhibitor or tamoxifen). Non-limiting examples of aromatase inhibitors include anastrozole, letrozole, and exemestane. In some embodiments, a CDK4 / 6 inhibitor is included as part of neoadjuvant or adjuvant therapy, and the patient's progression event must occur > 12 months after completion of the CDK4 / 6 inhibitor portion of neoadjuvant or adjuvant therapy.

[0132] In one embodiment of the methods described herein, the patient had been treated with one or more cancer therapies prior to administration of the combination therapy described herein. In one embodiment of the methods described herein, prior therapy included fulvestrant and / or palbociclib. In another embodiment, the patient described herein had not previously received treatment with fulvestrant, a PI3K inhibitor, and / or a CDK4 / 6 inhibitor.

[0133] In one embodiment of the methods described herein, a patient with breast cancer as described herein is resistant to one or more cancer therapies, such as CDK4 / 6 inhibitors like palbociclib, ribociclib, or abeciclib. In one embodiment of the methods described herein, resistance to cancer therapies includes recurrent or refractory cancer. Recurrence can refer to the reappearance of cancer at the original or new site after treatment. In one embodiment of the methods described herein, resistance to cancer therapies includes cancer progression during treatment with anticancer therapies. In some embodiments of the methods described herein, resistance to cancer therapies includes cancer that does not respond to treatment. The cancer may be resistant at the start of treatment or during treatment. In some embodiments of the methods described herein, the cancer is in an early or late stage.

[0134] The co-administration of enoxaparin with palbociclib and fulvestrant can prevent or delay the development of resistance in tumors (e.g., breast cancer) to CDK4 / 6 inhibitors (e.g., palbociclib, ribociclib, or abeciclib) or a combination of CDK4 / 6 inhibitors (e.g., palbociclib, ribociclib, or abeciclib) and fulvestrant. Therefore, a method for preventing or delaying the development of resistance in cancers (e.g., breast cancer) to therapies containing CDK4 / 6 inhibitors (e.g., palbociclib, ribociclib, or abeciclib) is provided, the method comprising administering the combination therapy detailed herein. In some embodiments, a method for preventing or delaying the development of resistance in tumors (e.g., breast cancer) to the therapy containing palbociclib is provided, the method comprising administering a combination therapy comprising enoxaparin, palbociclib, and fulvestrant. In some embodiments, the combination therapy is administered according to any method detailed herein.

[0135] In one embodiment, the patient described herein had been pretreated with an aromatase inhibitor (e.g., anastrozole, letrozole, or exemestane) or tamoxifen prior to administration of the combination therapy described herein. In one such embodiment, the patient relapsed during prior treatment with an aromatase inhibitor or tamoxifen or otherwise exhibited disease progression after such administration. In one such embodiment, relapse or disease progression was observed during the first 12 months of adjuvant endocrine therapy. In one embodiment, the prior treatment was with one or more aromatase inhibitors as described herein. In another embodiment, the prior treatment was with tamoxifen. In yet another such embodiment, the prior treatment was for locally advanced or metastatic breast cancer. In one such embodiment, the patient described herein had been pretreated with letrozole, tamoxifen, anastrozole, or exemestane. In another such embodiment, the patient described herein had been treated with an aromatase inhibitor or tamoxifen for 3–6 years prior to administration of the combination therapy described herein. In yet another such embodiment, the patient described herein had been treated with an aromatase inhibitor or tamoxifen for more than 6 years prior to administration of the combination therapy described herein. In yet another embodiment, the patient described herein was postmenopausal. In another embodiment, the patient described herein has at least one measurable lesion as measured by, for example, RECIST.

[0136] In one embodiment of the methods described herein, patients with hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, as described herein, may have already undergone surgical treatment prior to administration of the combination therapy described herein, such as breast-conserving surgery (i.e., mass resection focusing on removal of the primary tumor and margins) or more extensive surgery (i.e., mastectomy aimed at complete removal of all breast tissue). In another embodiment, patients described herein may undergo surgical treatment after treatment with the combination therapy described herein.

[0137] Radiation therapy is typically administered postoperatively to the breast / chest wall and / or regional lymph nodes to kill any remaining microscopic cancer cells. In the case of breast-conserving surgery, radiation is administered to the remaining breast tissue and sometimes to regional lymph nodes (including axillary lymph nodes). In the case of mastectomy, radiation may still be administered if there are factors predicting a high risk of local recurrence. In some embodiments of the methods provided herein, patients with hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, as described herein, may have received radiation therapy prior to administration of the combination therapy described herein. In other embodiments of the methods provided herein, patients with hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer, as described herein, may have received radiation therapy after administration of the combination therapy described herein.

[0138] In another embodiment, the patient has not been pretreated with a PI3K inhibitor. In yet another embodiment, the patient has not been pretreated with an mTOR inhibitor. In yet another embodiment, the patient has not been pretreated with an AKT inhibitor. In yet another embodiment, the patient has not previously received a cytotoxic chemotherapy regimen for metastatic breast cancer. In yet another embodiment, the patient described herein has not previously been treated with SERDs (selective estrogen receptor degraders), including, for example, fulvestrant.

[0139] This article also provides methods for inhibiting tumor growth or inducing tumor regression in the patients described herein, which are achieved by administering the combination therapies described herein.

[0140] In one embodiment, this document provides a method for producing or improving tumor regression in a patient suffering from the conditions described herein, achieved by administering a combination therapy comprising the methods described herein.

[0141] The development of combination therapies presents challenges, including, for example, the selection of agents for combination therapies that can improve efficacy while maintaining acceptable toxicity. A particular challenge is the need to differentiate the incremental toxicity of the combination. In one embodiment of the methods described herein, the combination therapies (e.g., enoxaparin, fulvestrant, and palbociclib) are administered with a dosing regimen that includes staggered dosing times. In one embodiment, the combination therapies (e.g., enoxaparin, fulvestrant, and palbociclib) are administered concurrently over a 28-day cycle.

[0142] In one embodiment of the method provided herein, enoxacillin is administered on each day of the QD in each 28-day cycle, and palbociclib is administered on days 1 through 21 of each 28-day cycle. In such embodiments, fulvestrant is administered, for example, on days 1 and 15 of the first 28-day cycle and on day 1 of every subsequent 28-day cycle, as described herein.

[0143] In some embodiments, the patient has adequate blood and organ function within 14 days prior to the start of the study treatment.

[0144] In patients at risk or prone to hyperglycemia (e.g., obese or prediabetic patients), metformin can be administered to control hyperglycemia. Therefore, in some embodiments, a method is provided for treating hormone receptor-positive and HER2-negative locally advanced or metastatic breast cancer in patients with PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer, the method comprising administering a combination therapy comprising enoxaparin, palbociclib, and fulvestrant to the patient, wherein the patient has previously received metformin treatment. In some embodiments, the method comprises administering metformin, enoxaparin, palbociclib, and fulvestrant, wherein enoxaparin, palbociclib, and fulvestrant are administered according to any of the methods detailed herein. In some of these embodiments, prior to administration of enoxaparin, the dose or regimen of metformin is adjusted to reduce, stabilize, or eliminate hyperglycemia in the patient. In some of these examples, metformin (500 mg to 2000 mg, e.g., 500 mg) is administered daily to the patient for approximately 15 days prior to administration of enoxaparin. In some of these examples, metformin (500 mg to 2000 mg, e.g., 500 mg) is administered daily to the patient for approximately 15 days prior to administration of palbociclib and fulvestrant, followed by administration of enoxaparin. In some of these examples, enoxaparin, palbociclib, and fulvestrant are administered according to the dosing regimen detailed herein.

[0145] Biomarker Breast cancer is a heterogeneous disease with many different subtypes, defined by molecular markers and various mutational signatures. In one embodiment, the PIK3CA / AKT1 / PTEN alteration status of a patient can be detected. In one embodiment, one or more of the following can be detected in the patients described herein: homophosphatase-tensin (PTEN) mutation, PTEN expression loss, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) mutation, protein kinase B α (AKT1) mutation, or a combination thereof. In one embodiment, the loss of PTEN expression is hemizygous or homozygous. In another embodiment, samples from the patients described herein can be evaluated for other biomarkers to identify factors that may be related to the safety and efficacy of the investigational treatment.

[0146] In one embodiment of the methods described herein, DNA may be obtained from blood samples and tumor tissues of the patients described herein using NGS, whole-genome sequencing (WGS), other methods, or combinations thereof. Such samples may be analyzed to identify germline (e.g., BRCA1 / 2) and somatic alterations that may predict response to an investigational drug, be associated with progression to a more severe disease state, be associated with acquired resistance to an investigational drug, or may contribute to knowledge and understanding of the biology of the disease. In another embodiment of the methods described herein, the patients described herein may have cancers characterized by activation of PI3K / Akt signaling, such as mutations in activated PIK3CA or AKT1, and alterations via PTEN, such as those provided herein. In another embodiment, NGS assays will be used to determine the tumor status of PIK3CA / AKT1 / PTEN alterations (e.g., Foundation Medicine, Inc. [FMI]). Review and response measures for the status of PIK3CA / AKT1 / PTEN alterations in archived tissues may be carried out on an ongoing basis. The expression of biomarkers such as PTEN provided herein can be measured using techniques known in the art, such as immunohistochemistry (IHC).

[0147] Circulating tumor DNA (ctDNA) can be detected in the blood of cancer patients with epithelial carcinoma and has diagnostic and therapeutic significance (Schwarzenbach et al. 2011). For example, the mutational status of tumor cells can be obtained by isolating ctDNA (Maheswaran S et al., N Engl J Med 2008;359:366-77), and ctDNA has been used to monitor the treatment efficacy of melanoma (Shinozaki M et al., Clin Cancer Res 2007;13:2068-74). Blood samples from the patients described herein can be collected at screening, at the initial tumor assessment, and / or at the study completion / early termination visit. In one embodiment, these samples are used to assess oncogene alterations at baseline and to evaluate the likelihood of new alterations following treatment with inaliprexate, palbociclib, and fulvestrant.

[0148] Example Abbreviations: AE, adverse events; AUC 0–24 Area under the concentration-time curve from 0 to 24 hours; BMI: Body Mass Index; CDK4 / 6i, cyclin-dependent kinase 4 / 6 inhibitors; CI, confidence interval; C max Maximum serum concentration; CR, complete response; ctDNA: Circulating tumor DNA; D, Heaven; ECOG, Eastern Cooperative Oncology Group; GMR, Geometric Mean Ratio; HbA1c, glycated hemoglobin; HER2, human epidermal growth factor receptor 2; MAF, Mutant Allele Frequency; MBC, metastatic breast cancer; MTD, Maximum Tolerable Dose; NCI-CTCAE, the National Cancer Institute's Common Terminology Standard for Adverse Events; NE, not evaluable; PD, pharmacodynamics; PrD, a progressive disease; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α; PK, pharmacokinetics; PR, partial response; pts, patient RECIST, the criteria for evaluating the efficacy of treatment in solid tumors; SD, stable disease; SLD, the sum of the longest diameters; TRAE, treatment-related adverse events.

[0149] Example 1 Phase 3 clinical study of the combination of inalisertib / palbociclib / fulvestrant A multicenter, international, phase III randomized, double-blind, placebo-controlled study (INAVO120) was conducted to evaluate the efficacy and safety of inaritase in combination with palbociclib and fulvestrant compared with placebo plus palbociclib and fulvestrant in patients with PIK3CA-mutated, hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer whose disease progressed during treatment or within 12 months after completion of adjuvant endocrine therapy and who had not previously received systemic therapy for metastatic disease.

[0150] The study design is shown in Figure 1. This multicenter study included 325 patients who were randomized to either the study treatment group or the control treatment group. PIK3CA mutation positivity was identified in 270 patients using the F1LCDx assay performed at Foundation Medicine, Inc. (FMI). The primary endpoint was investigator-assessed progression-free survival, defined as the time from randomization in the clinical trial to disease progression or death from any cause; 85% statistical power, two-sided α = 0.05; the primary analysis was planned at approximately 194 events. Secondary endpoints included overall survival (OS was tested only when PFS was positive; interim OS analysis was performed during the primary PFS analysis), PFS of BICR, objective response rate (ORR), clinical benefit rate (CBR), best overall response (BOR), duration of response (DOR), patient-reported outcome (PRO), and safety.

[0151] Stratification factors included (a) visceral disease (yes or no); (b) endocrine resistance (primary vs. secondary), defined according to the 4th European Academy of Oncology (ESO)-European Society for Medical Oncology (ESMO) International Consensus Guidelines for Advanced Breast Cancer; primary: recurrence within the first 2 years of adjuvant endocrine therapy (ET); secondary: recurrence at least 2 years after adjuvant ET or within 12 months after completion of adjuvant ET; and (c) region (North America / Western Europe; Asia; other).

[0152] The study met its primary endpoint of progression-free survival (PFS), demonstrating a statistically significant and clinically meaningful improvement compared to palbociclib and fulvestrant alone. The inalipase combination reduced the risk of disease progression or death (PFS) by more than 50% compared to palbociclib and fulvestrant alone. A clear positive trend was observed in the total survival (OS) data available to date. Available data from other secondary endpoints showed clinically meaningful increases in ORR, DOR, and CBR in the primary analysis. The inalipase combination was well tolerated. The most common grade 3 to 4 adverse events (≥ 5%) with the inalipase combination compared to palbociclib and fulvestrant alone were neutropenia, thrombocytopenia, anemia, stomatitis, and hyperglycemia.

[0153] Researchers assessed progression-free survival (PFS) in 270 patients identified as PIK3CA mutation-positive by central FMI testing, and Table A1 lists several key subgroups. Figure 2 shows the Kaplan-Meier (KM) plot of PFS. Figure 3 shows the KM plot of OS trends at the interim analysis. In this interim analysis, the predetermined boundary for significant OS benefit was not crossed (p<0.0098). Researchers assessed that the ORR and CBR were increased by approximately 30% in the enoxacillin group compared to the control group. Figure 4 shows the KM plot of DOR in 111 responsive patients identified as PIK3CA mutation-positive by central FMI testing, showing a median DOR of approximately 18–19 months in the enoxacillin group compared to a median DOR of approximately 9–10 months in the control group.

[0154] Table A1 Grouping and intervention Experimental group: Inaricept + Palbociclib + Fluvestralc Participants received: (a) oral enoxacillin from day 1 to day 28 of each 28-day cycle; (b) oral palbociclib from day 1 to day 21 of each 28-day cycle; and (c) intramuscular (IM) fulvestrant approximately every 4 weeks.

[0155] Placebo control group: Placebo + Palbociclib + Fulvestrant Participants received: (a) oral placebo from day 1 to day 28 of each 28-day cycle; (b) oral palbociclib from day 1 to day 21 of each 28-day cycle; and (c) intramuscular (IM) fulvestrant approximately every 4 weeks.

[0156] Outcome measures Initial outcome measures : 1. Progression-free survival (PFS) [Timeframe: From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (maximum 6 years)] The results showed that the combination of inalixeil with palbociclib and fulvestrant improved progression-free survival in the first-line setting.

[0157] Second outcome measures : 2. Objective Response Rate (ORR) [Timeframe: Maximum 6 years] 3. Optimal Overall Response Rate (BOR) [Timeframe: Maximum 6 years] 4. Duration of Relief (DOR) [Timeframe: From the first achievement of CR or PR to the first occurrence of disease progression or death from any cause, whichever occurs first (maximum 6 years)] 5. Clinical Benefit Rate (CBR) [Timeframe: Maximum 6 years] 6. Total OS [Timeframe: From randomization to death from any cause (maximum 6 years)] 7. Time to Pain Worsening (TTD) [Timeframe: Treatment: Day 1 of cycles 1 through 3, then Day 1 of every other cycle until treatment is discontinued. Post-treatment: Once every 8 weeks for 2 years, then once every 12 weeks until the end of the study (maximum 6 years)] 8. Body Functioning Tolerance (TTD) [Timeframe: Treatment: Day 1 of cycles 1 through 3, then Day 1 of every other cycle until treatment is discontinued. Post-treatment: Once every 8 weeks for 2 years, then once every 12 weeks until the end of the study (maximum 6 years)] 9. Role Function TTD [Timeframe: Treatment: Day 1 of cycles 1 through 3, then Day 1 of every other cycle until treatment is discontinued. Post-treatment: Once every 8 weeks for 2 years, then once every 12 weeks until the end of the study (maximum 6 years)] 10. Total Physical and Mental Health (TTD) [Timeframe: Treatment: Day 1 of cycles 1 through 3, then Day 1 of every other cycle until treatment is discontinued. Post-treatment: Once every 8 weeks for 2 years, then once every 12 weeks until the end of the study (maximum 6 years)] 11. Percentage of participants who experienced adverse events [Timeframe: From randomization to study completion (maximum 6 years)] 12. Plasma concentration of inalice [Timeframe: A predefined time interval from baseline to the end of the study (maximum 6 years)] 13. Plasma concentration of palbociclib [Timeframe: A predefined time interval from baseline to the end of the study (maximum 6 years)] 14. Plasma concentration of fulvestrant [Timeframe: A predefined time interval from baseline to the end of the study (maximum 6 years)] Eligibility In one embodiment of this study, patients aged 18 years or older were included; all sexes were accepted (not based on sex). Healthy volunteers were not accepted. The inclusion and exclusion criteria for the target population are as follows.

[0158] Inclusion criteria A confirmed diagnosis of HR+ / HER2- breast cancer Metastatic or locally advanced disease that is not suitable for curative treatment Disease progression during adjuvant endocrine therapy or within 12 months of completion of adjuvant endocrine therapy (using aromatase inhibitors or tamoxifen). If you are premenopausal / perimenopause, receive LHRH agonist therapy for at least 2 weeks prior to day 1 of cycle 1. Biomarker qualification (detection of a specified mutation in PIK3CA via a designated test) Agree to provide fresh or archived tumor tissue specimens According to the criteria for evaluating the efficacy of treatment for solid tumors, version 1.1, measurable diseases are eligible; "bone-only" diseases, even if considered measurable, do not qualify. The Eastern Oncology Collaborative Group's activity status is 0 or 1. Life expectancy > 6 months Sufficient blood and organ function were maintained for 14 days prior to the start of the treatment study. Exclusion criteria Metaplastic breast cancer Any history of pia mater disease or carcinomatous meningitis Any prior systemic therapy for metastatic breast cancer Previous treatment with fulvestrant or any selective estrogen receptor degrader Previous treatment with any PI3K, AKT, or mTOR inhibitors, or any medication whose mechanism of action inhibits the PI3K-AKT-mTOR pathway. Type 2 diabetes or any history of type 1 diabetes requiring continuous systemic treatment at the start of the study. Known or untreated, or active CNS metastases. Patients with a history of treated CNS metastases are eligible for inclusion. During the study and treatment period, patients with active inflammatory or infectious conditions or any eye disease requiring surgery should undergo the procedure. Symptomatic active lung disease, or requiring daily oxygen therapy History of inflammatory bowel disease or active colitis Received anticancer therapy within 2 weeks prior to entering the study Randomization group members who had received one or more investigational drugs within the previous 4 weeks For patients with >= 25% bone marrow or hematopoietic stem cells or bone marrow transplantation following prior radiotherapy Chronic corticosteroid therapy or immunosuppressants Pregnancy, breastfeeding, or planning pregnancy during the study period or within 60 days after the last dose of the study treatment drug. Major surgery or significant traumatic injury within 28 days prior to day 1 of cycle 1 Example 2 Additional analysis of the INAVO120 study Additional analyses were performed on the results of the INAVO120 Phase 3 study. In addition to efficacy endpoints including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), best overall response (BOR), clinical benefit rate (CBR), and duration of response (DOR), the time from randomization to termination or discontinuation of next-line treatment or death from any cause (representing PFS2), the time from randomization to the first subsequent chemotherapy after discontinuation of treatment, and the time to confirmed clinically significant deterioration (TTCD) were also assessed. Safety endpoints and patient-reported outcomes (PRO) endpoints were also evaluated.

[0159] Statistical methods: For efficacy endpoints and TTCD, hazard ratios were estimated using a Cox proportional hazards model with 95% CI, and the median was estimated using the Kaplan-Meier method with the Brookmeyer-Crowley method applied for 95% CI. The clinical cutoff date (CCOD) was September 29, 2023; the median follow-up time was 21.3 months.

[0160] INAVO120 met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival (PFS) (15.0 months vs. 7.3 months; hazard ratio, 0.43 [95% CI 0.32–0.59]; p<0.0001). See also Figure 5 .

[0161] Inaricel, palbociclib, and fulvestrant were associated with sustained benefit after disease progression, demonstrating a delay in the need for subsequent therapies (Δ 8.9 months), including chemotherapy (NE vs 15.0 months), and supporting the clinical benefit of inaricel-based therapies.

[0162] The median time from randomization to termination or discontinuation of next-line treatment or death from any cause (which is representative of PFS2 (time from randomization to the next progression or death from any cause after discontinuation of study treatment due to progressive disease) was 24.0 (95% CI 18.6–NE) months in the inalipse group and 15.1 (95% CI 13.5–22.3) months (Δ 8.9 months) in the placebo group, with a stratified hazard ratio of 0.54 (95% CI 0.38–0.77). See Figure 6. The median time from randomization to the first subsequent chemotherapy after discontinuation of treatment was non-evaluable (95% CI 24.8–NE) months in the inalipse group and 15.0 (95% CI 10.6–24.8) months in the placebo group, with a stratified hazard ratio of 0.54 (95% CI 0.37–0.78). See Figure 7.

[0163] Post-progression therapies are listed in the table below.

[0164] One patient in the placebo group received a treatment unrelated to breast cancer (cytarabine). † This includes less common HR+ therapies, such as PARP inhibitors and HER2-targeted therapies.

[0165] Study endpoints Key selected adverse events, including hyperglycemia, diarrhea, rash, and stomatitis / mucosal inflammation, were assessed using grouping terminology; severity was reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The number of patients with at least one adverse event (AE) in the enoxacillin group and the placebo group, and the time of first occurrence of the AE in the enoxacillin group (if the AE had resolved and recurred in the same patient, it was not included in this dataset for a second occurrence), are as follows: The graphical representation is shown in Figure 8. By the time of CCOD, most of the key selected AEs had been eliminated ("elimination" is based on the investigator's decision); some patients were enrolled close to CCOD and are currently being followed up on AEs.

[0166] The number of patients in the enoxacillin group who experienced interruption, reduction, or discontinuation of enoxacillin treatment due to key selected adverse events (AEs) is shown in the table below.

[0167] One patient in the inalice group discontinued treatment due to an adverse event (AE) of type 2 diabetes, which was not recorded under hyperglycemic conditions.

[0168] The discontinuation rate of enoxacillin due to any adverse events was 6.2%. The low rate of discontinuation due to hyperglycemia, diarrhea, rash, and stomatitis / mucosal inflammation confirms the manageable safety and tolerability of enoxacillin.

[0169] The patient received concomitant medication for the adverse event. The following lists the number of patients who received concomitant medication for key selected AEs and the most common concomitant medication for each AE.

[0170] Patient-reported outcome endpoints Patient-reported outcome endpoints were assessed on day 1 of cycles 1–3, on day 1 of every subsequent cycle (cycles 5, 7, 9, etc.), at treatment discontinuation, and every 3 months during survival follow-up. Baseline completion rates for all assessments were >90% in both groups; post-baseline completion rates remained >80% in both groups up to cycle 15; <50% of intention-to-treat samples were retained at cycle 9 in the enoxacillin group and at cycle 5 in the placebo group.

[0171] Compared with the placebo group, patients in the enoxacillin group experienced a longer time to unconfirmed, clinically significant worsening of pain severity. The time to confirmed, clinically significant worsening at the highest pain severity level was assessed using the Brief Pain Scale-Short Form (BPI-SF). The median time was 30.9 (95% CI 16.6–NE) months in the enoxacillin group and 18.1 (95% CI 13.1–NE) months in the placebo group (Δ 12.8 months), with a hazard ratio of 0.74 (95% CI 0.48–1.13). See Figure 9.

[0172] Symptomatic toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) based on patient-reported outcomes. Most patients reported moderate or lower levels of most severe post-baseline symptomatic toxicity. Patients in the inalice group experienced higher (worse) levels of diarrhea, oral ulcers, and rash compared to the placebo group. The percentage of patients based on baseline and worst post-baseline PRO-CTCAE scores is shown in Figure 10.

[0173] When asked, "How bothered have you been by the side effects of your treatment in the past 7 days?", most patients reported "none" or "very little" overall "bothered" by the treatment. The percentage of patients in each "bothered" category during treatment is shown in Figure 11.

[0174] Patient-reported outcome data showed that patients who received enoxaparin in addition to fulvestrant and palbociclib experienced a longer median time to worsening pain severity (Δ 12.8 months), maintained daily functioning and health-related quality of life (HRQoL) during treatment, and experienced minimal increase in treatment burden. HRQoL, physical function, and role functioning remained at baseline levels in both groups. Adding enoxaparin had no adverse effects on patients' physical function, role functioning, or HRQoL.

[0175] Example 3 Prescribing information for ITOVEBI™ (inavolisib) A New Drug Application (NDA) has been submitted to the U.S. FDA based on the results of the INAV120 study. Below is the prescribing information from a draft label version prior to approval.

[0176] Complete Prescription Information 1. Indications and Uses ITOVEBI, in combination with palbociclib and fulvestrant, is indicated for the treatment of endocrine resistance that has relapsed during or after adjuvant endocrine therapy. PIK3CA Adults with mutated, hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative, locally advanced or metastatic breast cancer (as detected by an FDA-approved test). [See Clinical Studies (14.1)] .

[0177] 2. Dosage and administration 2.1 Patient selection Based on the presence of one or more in the plasma sample PIK3CA In cases of mutation, patients selected for ITOVEBI treatment with HR-positive, HER2-negative, locally advanced, or metastatic breast cancer are considered. [See Clinical Studies (14.1)] .

[0178] Regarding FDA-approved drugs for detecting breast cancer PIK3CA For mutation detection information, please visit: www.fda.gov / companiondiagnostics.

[0179] 2.2 Recommended evaluation before starting ITOVEBI Assess fasting plasma glucose (FPG) / blood glucose (FBG) and hemoglobin A. 1C (HbA 1C And optimize blood glucose regularly before starting ITOVEBI and during treatment. [See Warnings and Precautions (5.1)] .

[0180] 2.3 Recommended dose The recommended dose of ITOVEBI is 9 mg orally once daily, with or without food, until disease progression or unacceptable toxicity occurs.

[0181] Patients are advised to take ITOVEBI at approximately the same time each day.

[0182] Swallow ITOVEBI tablets whole. Do not chew, crush, or break them before swallowing.

[0183] If a patient misses a dose, instruct them to take the missed dose as soon as possible within 9 hours. If more than 9 hours have passed, instruct the patient to skip the missed dose and take the next dose at the scheduled time.

[0184] If the patient vomits after taking one dose, instruct the patient not to take an extra dose that day and to resume the normal dosing schedule the following day.

[0185] ITOVEBI is administered in combination with palbociclib and fulvestrant. The recommended dose of palbociclib is 125 mg orally once daily for 21 consecutive days, followed by a 7-day break to constitute a 28-day cycle. For dosing information on palbociclib and fulvestrant, please refer to the complete prescribing information.

[0186] For premenopausal and perimenopausal women, luteinizing hormone-releasing hormone (LHRH) agonists are administered according to local clinical practice.

[0187] For men, LHRH agonists should be considered based on local clinical practice.

[0188] 2.4 Dose adjustment for adverse reactions Recommended dose reduction levels for ITOVEBI in response to adverse reactions are listed in Table 1. If a patient cannot tolerate a second dose reduction, ITOVEBI should be permanently discontinued.

[0189] Table 1: Dosage Reduction for Adverse Reactions Recommended dosage adjustments for ITOVEBI in response to adverse reactions are summarized in Table 2.

[0190] Table 2: Recommended Dosage Adjustments for Adverse Reactions 2.5 Dose adjustment for moderate renal impairment For patients with moderate renal impairment (eGFR of 30 to <60 mL / min based on CKD-EPI), the recommended starting dose of ITOVEBI is 6 mg orally once daily. [See Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)] .

[0191] 3. Dosage form and specifications tablet: 3 mg: Red convex shape with "INA 3" embossed on one side.

[0192] 9 mg: Pink oval shape with "INA 9" embossed on one side.

[0193] 4. Contraindications none.

[0194] 5 Warnings and Precautions 5.1 Hyperglycemia Severe hyperglycemia may occur in patients receiving ITOVEBI treatment.

[0195] Eighty-five percent of patients treated with ITOVEBI experienced elevated fasting blood glucose, including 22% of patients with grade 2 (FPG > 160 to 250 mg / dL), 12% with grade 3 (FPG > 250 to 500 mg / dL), and 0.6% with grade 4 (FPG > 500 mg / dL).

[0196] In INAVO120, 46% (74 / 162) of patients receiving ITOVEBI received oral antihyperglycemic agents, and 7% (11 / 162) received insulin therapy to control elevated fasting blood glucose. Among patients with elevated fasting blood glucose >160 mg / dL, 96% (52 / 54) experienced at least one grade improvement in fasting blood glucose, with a median time from the first event to improvement of 8 days (range: 2 to 43 days).

[0197] In patients with hyperglycemia, the median time to first onset was 7 days (range: 2 to 955 days). Hyperglycemia led to dose interruption in 28% of patients, dose reduction in 2.5%, and discontinuation of ITOVEBI in 1.2% of patients.

[0198] The safety of ITOVEBI in patients with type 1 diabetes or type 2 diabetes requiring continuous antihyperglycemic therapy has not been investigated.

[0199] Before starting ITOVEBI treatment, fasting blood glucose levels (FPG or FBG) and HbA1c should be measured. 1C Levels and optimize fasting blood glucose.

[0200] In patients who develop hyperglycemia after starting ITOVEBI treatment, or in patients who develop hyperglycemia after starting ITOVEBI treatment, fasting blood glucose levels should be monitored or self-monitored every 3 days during the first week (days 1-7), then weekly for the next 3 weeks (days 8-28), then every 2 weeks for the next 8 weeks, and then every 4 weeks thereafter, as directed by clinical instructions. HbA1c should be monitored every 3 months. 1C And monitor according to clinical instructions.

[0201] Use antihyperglycemic medications as directed by clinical indications to control hyperglycemia. Continue to monitor fasting blood glucose levels during antihyperglycemic medication treatment. Patients with a history of well-controlled type 2 diabetes may require intensified antihyperglycemic therapy and close monitoring of fasting blood glucose levels.

[0202] Consider consulting a healthcare professional experienced in treating high blood sugar and starting at-home fasting blood glucose monitoring for patients with risk factors for high blood sugar or who have experienced high blood sugar. Advise patients to pay attention to the signs and symptoms of high blood sugar and provide them with counseling on lifestyle changes.

[0203] Depending on the severity of hyperglycemia, ITOVEBI may require dose interruption, reduction, or discontinuation. [See Dosage and Administ ration (2.4)] .

[0204] 5.2 Stomatitis Severe stomatitis may occur in patients receiving ITOVEBI treatment.

[0205] Stomatitis occurred in 51% of patients receiving ITOVEBI in combination with palbociclib and fulvestrant, including grade 3 events in 6% of patients. The median time to first onset was 13 days (range: 1 to 610 days).

[0206] Stomatitis led to dose interruption of ITOVEBI in 10% of patients, dose reduction in 3.7% and discontinuation of ITOVEBI in 0.6% of patients.

[0207] Among patients receiving ITOVEBI in combination with palbociclib and fulvestrant, 38% used mouthwash containing corticosteroids to control or prevent stomatitis.

[0208] Monitor patients for signs and symptoms of stomatitis. Depending on the severity, pause, reduce the dosage, or permanently discontinue ITOVEBI. [See Dosage and Administration (2.4)] .

[0209] 5.3 Diarrhea Severe diarrhea, including dehydration and acute kidney injury, may occur in patients receiving ITOVEBI treatment.

[0210] Diarrhea occurred in 48% of patients receiving ITOVEBI in combination with palbociclib and fulvestrant, including grade 3 events in 3.7% of patients. The median time to first onset was 15 days (range: 2 to 602 days). Among patients receiving ITOVEBI in combination with palbociclib and fulvestrant, 28% (46 / 162) used antidiarrheal medications to control symptoms. 7% of patients required dose interruption, and dose reduction occurred in 1.2% of patients.

[0211] Monitor the patient for signs and symptoms of diarrhea. Advise the patient to increase oral rehydration and initiate antidiarrheal treatment upon the first sign of diarrhea while taking ITOVEBI. Suspend, reduce the dose, or permanently discontinue ITOVEBI depending on the severity. [See Dosage and Administration (2.4)] .

[0212] 5.4 Embryo-fetal toxicity Based on its findings in animals and its mechanism of action, ITOVEBI can cause fetal harm when administered to pregnant women. [See Clinical Pharmacology (12.1)]In an animal reproduction study, oral administration of enoxacillin to pregnant rats during organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality, structural abnormalities, and growth alterations at maternal exposure levels (based on the area under the curve (AUC) approximately equal to the recommended dose of 9 mg / day for human exposure).

[0213] Inform pregnant women and women of reproductive potential of the potential risks to the fetus. Women of reproductive potential are advised to use effective non-hormonal contraception during ITOVEBI treatment and for one week after the last dose. Male patients whose female partners are of reproductive potential are advised to use effective contraception during ITOVEBI treatment and for one week after the last dose. [See Use in Specific Populations (8.1 and 8.3)] .

[0214] ITOVEBI is used in combination with palbociclib and fulvestrant. Please refer to the full prescribing information for palbociclib and fulvestrant for pregnancy and contraception information.

[0215] 6. Adverse Reactions The following adverse reactions are discussed in more detail in other parts of the label: High blood sugar [See Warnings and Precautions (5.1)] Stomatitis [See Warnings and Precautions (5.2)] diarrhea [See Warnings and Precautions (5.3)] 6.1 Clinical trial experience Because clinical trials are conducted under widely different conditions, the adverse reaction rate observed in a clinical trial of one drug cannot be directly compared with the adverse reaction rate observed in a clinical trial of another drug, and may not reflect the adverse reaction rate observed in practice.

[0216] Locally advanced or metastatic breast cancer INAVO120 In a study of 324 patients PIK3CA The safety of ITOVEBI was evaluated in a randomized, double-blind, placebo-controlled study (INAVO120) in patients with HER2-positive, HER2-negative locally advanced or metastatic breast cancer. [See Clinical Studies (14.1)] .

[0217] Patients received either ITOVEBI 9 mg (n=162) or placebo (n=162) in combination with palbociclib and fulvestrant. In the ITOVEBI combination with palbociclib and fulvestrant group, the median duration of ITOVEBI treatment was 9 months (range: 0 to 39 months).

[0218] Serious adverse events occurred in 24% of patients receiving ITOVEBI in combination with palbociclib and fulvestrant. Serious adverse events occurring in ≥ 1% of patients included anemia (1.9%), diarrhea (1.2%), and urinary tract infection (1.2%).

[0219] In patients receiving ITOVEBI in combination with palbociclib and fulvestrant, 3.7% of patients experienced fatal adverse events, including (0.6% each) acute coronary syndrome, cerebral hemorrhage, cerebrovascular accident, COVID-19 infection, and gastrointestinal bleeding.

[0220] Six percent of patients permanently discontinued ITOVEBI due to adverse reactions. Adverse reactions leading to permanent discontinuation of ITOVEBI included hyperglycemia (1.2%), and (each 0.6%) stomatitis, gastric ulcer, intestinal perforation, anal abscess, elevated ALT, weight loss, bone pain, musculoskeletal pain, transitional cell carcinoma, and acute kidney injury.

[0221] 69% of patients discontinued their ITOVEBI dose due to adverse reactions. Adverse reactions requiring dose discontinuation in ≥ 2% of patients included hyperglycemia (28%), neutropenia (23%), COVID-19 infection (16%), stomatitis (10%), diarrhea (7%), thrombocytopenia (4.9%), anemia (4.3%), upper respiratory tract infection (4.3%), leukopenia (3.7%), fever (3.1%), nausea (2.5%), and fatigue (2.5%).

[0222] 14% of patients had to reduce their ITOVEBI dose due to adverse reactions. In ≥ 2% of patients, the adverse reactions requiring a dose reduction of ITOVEBI were stomatitis (3.7%) and hyperglycemia (2.5%).

[0223] The most common (≥ 20%) adverse reactions (including laboratory abnormalities) are neutropenia, hemoglobin deficiency, elevated fasting glucose, thrombocytopenia, lymphopenia, stomatitis, diarrhea, calcium deficiency, fatigue, potassium deficiency, elevated creatinine, elevated ALT, nausea, sodium deficiency, magnesium deficiency, rash, decreased appetite, COVID-19 infection, and headache.

[0224] Adverse reactions and laboratory abnormalities observed with INAVO120 are summarized in Tables 3 and 4, respectively. Patient-reported symptoms are summarized in Table 5.

[0225] Table 3: Adverse reactions in INAVO120 (incidence ≥ 10%, and ≥ 5% [all grades] or ≥ 2% [grade 3-4] higher in the ITOVEBI group) Clinically relevant adverse reactions that occurred in <10% of patients receiving ITOVEBI in combination with palbociclib and fulvestrant included abdominal pain, dry eye, taste disturbances, and dyspepsia.

[0226] Table 4: Selected laboratory abnormalities in INAVO120 (incidence ≥ 10%, and ≥ 2% higher in the ITOVEBI group [all grades or 3-4]) In INAVO120, patient-reported symptomatic toxicities (i.e., diarrhea, nausea, vomiting, fatigue, oral ulcers, decreased appetite, and rash) are assessed via the Patient-Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE) at baseline, every two weeks up to day 15 of cycle 3, and then on day 1 of every 28-day cycle thereafter until treatment is discontinued.

[0227] Completion rates were >90% at baseline in both groups and >80% at subsequent time points when >50% of randomized patients were still receiving treatment.

[0228] Table 5: Patient-reported symptoms assessed by PRO-CTCAE in INAV 120 The overall impact of patient-reported side effects was assessed using the Modified Bother Item (MBI). Patients responded to “I am bothered by the side effects of the treatment,” and at baseline, 70% of patients in the ITOVEBI vs. palbociclib and fulvestrant group had an MBI response of “completely none,” compared to 76% in the placebo vs. palbociclib and fulvestrant group. At day 15 of cycle 2, 25% of patients in the ITOVEBI vs. palbociclib and fulvestrant group had an MBI response of “completely none,” compared to 53% in the placebo vs. palbociclib and fulvestrant group. After 31 cycles of treatment, patients in the ITOVEBI vs. palbociclib and fulvestrant group reported more side effect bother compared to the placebo vs. palbociclib and fulvestrant group.

[0229] 8. Use in specific populations 8.1 Pregnancy Risk summary ITOVEBI is used in combination with palbociclib and fulvestrant. Please refer to the full prescribing information for palbociclib and fulvestrant for pregnancy information.

[0230] Based on animal data and its mechanism of action, ITOVEBI can cause fetal harm when administered to pregnant women. [See Clin ical Pharmacology (....1)] There are no available data regarding the use of ITOVEBI in pregnant women to inform about the associated risks. In an animal reproductive study, oral administration of inalipse to pregnant rats during organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality, structural abnormalities, and growth alterations at maternal exposure levels (based on an AUC approximately equal to the recommended dose of 9 mg / day for human exposure). (See data) Inform pregnant women and women of reproductive potential about the potential risks to the fetus.

[0231] The background risk of major birth defects and miscarriage in the specified population is unclear. In the general U.S. population, the estimated background risk of major birth defects for clinically recognized pregnancies is 2% to 4%, while the estimated background risk of miscarriage is 15% to 20%.

[0232] Data Animal data In an embryo-fetal development study, pregnant rats received oral doses of enoxacillin up to 6 mg / kg / day during organogenesis. Administration of doses ≥ 2 mg / kg / day resulted in decreased fetal and placental weight, post-implantation loss, reduced fetal viability, fetal malformations (including kyphosis, thoracic vertebral arch fusion, and microphthalmia), and variations (including renal pelvis dilatation, short extra ribs, and wavy ribs). At a dose of 2 mg / kg / day, based on AUC, maternal exposure was 0.9 times the human exposure at the recommended dose of 9 mg / day.

[0233] 8.2 Lactation Risk summary ITOVEBI is used in combination with palbociclib and fulvestrant. Please refer to the full prescribing information for palbociclib and fulvestrant for information on breastfeeding.

[0234] Currently, there is no data on the presence of inalice or its metabolites in human milk, or their effects on milk production or breastfed infants. Due to the potential for serious adverse reactions in breastfed infants, it is recommended that breastfeeding women refrain from breastfeeding during ITOVEBI treatment and for one week after the last dose.

[0235] 8.3 Females and males of reproductive potential ITOVEBI is used in combination with palbociclib and fulvestrant. Please refer to the full prescribing information for palbociclib and fulvestrant for information on contraception and infertility.

[0236] When administered to pregnant women, ITOVEBI can cause fetal harm. [See Use in Specific Populations (8.1) ].

[0237] Pregnancy testing Before starting ITOVEBI treatment, verify the pregnancy status of women with reproductive potential.

[0238] Contraception female Women of reproductive potential are advised to use an effective non-hormonal contraceptive method during ITOVEBI treatment and for one week after the last dose.

[0239] male Male patients whose female partners are of reproductive potential are advised to use effective contraception during ITOVEBI treatment and for one week after the last dose.

[0240] Infertility Based on animal studies, ITOVEBI may impair the fertility of women and men of reproductive potential. [See Non clinical Toxicology (13.1)] .

[0241] 8.4 Pediatric use The safety and efficacy of ITOVEBI in pediatric patients have not been established.

[0242] 8.5 Geriatric use Of the 162 patients who received ITOVEBI in INAVO120, 15% were ≥ 65 years old and 3% were ≥ 75 years old.

[0243] Compared with younger patients, patients aged ≥ 65 years had a higher incidence of dose adjustment or discontinuation of ITOVEBI due to adverse reactions (79% and 68%, respectively).

[0244] Clinical studies of ITOVEBI did not include a sufficient number of patients aged ≥ 65 years to determine whether they had different responses compared to younger patients.

[0245] 8.6 Renal impairment Reduce the dose in patients with moderate renal impairment (eGFR 30 to <60 mL / min based on CKD-EPI). [See Dosage and Administration (2.5)] Dose adjustment is not recommended in patients with mild renal impairment (eGFR 60 to <90 mL / min). ITOVEBI has not been evaluated in patients with severe renal impairment (eGFR <30 mL / min).

[0246] 11. Explanation ITOVEBI contains enallixetine, a kinase inhibitor. The chemical name of enallixetine is (2S)-2-[[2-[(4S)-4-(difluoromethyl)-2-oxo-azolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazolidin-9-yl]amino]propionamide. Enallixetine is a white to off-white, grayish-pink, grayish-orange, or grayish-yellow powder or powder in lumps. Enallixetine exhibits pH-dependent water solubility; it has the highest solubility at low pH and decreases with increasing pH. The molecular formula of enallixetine is C2. 18 H 19 F₂N₅O₄, with a molecular weight of 407.37 g / mol. The chemical structure of inalice is shown below: ITOVEBI film-coated tablets are available for oral administration in two strengths containing 3 mg and 9 mg of inalilese. The tablets also contain lactose, magnesium stearate, microcrystalline cellulose, and sodium carboxymethyl starch. The film coating contains the following inactive ingredients: polyvinyl alcohol (partially hydrolyzed), titanium dioxide, polyethylene glycol / polyethylene glycol, talc, red iron oxide, and yellow iron oxide (only in the 9 mg tablet).

[0247] 12 Clinical Pharmacology 12.1 Mechanism of action Enalix is ​​a phosphatidylinositol 3-kinase (PI3K) inhibitor whose inhibitory activity primarily targets PI3Kα. In vitro, enalix induces mutations in the PI3K catalytic α subunit p110α (produced by…) PIK3CA The degradation of (gene-encoded) AKT inhibits phosphorylation of downstream target AKT, reduces cell proliferation, and in PIK3CA Induces apoptosis in mutant breast cancer cell lines. In vivo, innalisex reduces... PIK3CATumor growth in a xenograft model of mutant, estrogen receptor-positive breast cancer. The combination of inalipase with palbociclib and fulvestrant increased tumor growth inhibition compared to each treatment alone or in a two-drug combination.

[0248] 12.2 Pharmacodynamics Exposure-response relationship The exposure-response relationship for enoxacillin efficacy has not been fully characterized. The time course of the enoxacillin effect response is unclear. Higher systemic exposure to enoxacillin is associated with a higher incidence of grade ≥2 anemia, grade ≥2 hyperglycemia, and dose adjustments to enoxacillin due to adverse reactions.

[0249] Cardiac electrophysiology At the recommended approved dose, the likelihood of an average QTc interval increase of >20 ms is low.

[0250] 12.3 Pharmacokinetics Unless otherwise stated, the pharmacokinetics of enoxacillin are expressed as the geometric mean (geometric coefficient of variation [geo CV]%) after administration of the approved recommended dose. The steady-state AUC of enoxacillin is 10¹⁰ h⁻¹. ng / mL (25%), and C max The concentration was 69 ng / mL (27%). Steady-state concentration was expected to be reached on day 5.

[0251] Inalise accumulates approximately twice as much.

[0252] The steady-state AUC of inalixe is proportional to the dose from 6 to 12 mg (0.7 to 1.3 times the approved recommended dose).

[0253] Absorption rate The absolute oral bioavailability of enoxacillin is 76%. The steady-state median (minimum, maximum) time (T0) for enoxacillin to reach maximum plasma concentration is... max The duration is 3 hours (0.5, 4 hours).

[0254] Effect of food No clinically significant differences in the pharmacokinetics of enoxacillin were observed when it was administered in combination with a high-fat diet (approximately 1,000 calories, 50% fat).

[0255] Distribution The apparent (oral) volume of distribution of enoxacillin is 155 L (26%). Enallixil has a plasma protein binding rate of 37% and exhibits no concentration-dependent effect in vitro. The blood-to-plasma ratio of enoxacillin is 0.8.

[0256] Elimination The elimination half-life of inalice is 15 hours (24%), and the total clearance rate is 8.8 L / hr (29%).

[0257] Metabolism Enallise is primarily metabolized via hydrolysis. In vitro, enallise is minimally metabolized by CYP3A.

[0258] Excretion Following oral administration of a single dose of radiolabeled medication, 49% of the administered dose was recovered in urine (40% unchanged) and 48% was recovered in feces (11% unchanged).

[0259] Specific populations Based on age (27 to 85 years), sex, race (Asian or Caucasian), weight (39 to 159 kg), or mild hepatic impairment (total bilirubin > ULN to ≤ 1.5 × ULN or AST > ULN and total bilirubin ≤ ULN), no clinically significant differences in the pharmacokinetics of enoxacillin were observed. The effect of moderate to severe hepatic impairment on the pharmacokinetics of enoxacillin is unclear.

[0260] Patients with renal impairment Compared with patients with normal renal function (eGFR ≥ 90 mL / min), patients with moderate renal impairment had a 73% higher ininarise AUC.

[0261] No clinically significant differences in the pharmacokinetics of enoxalide were observed in patients with mild renal impairment compared to those with normal renal function. The effect of severe renal impairment (eGFR <30 mL / min) on the pharmacokinetics of enoxalide is unclear.

[0262] Drug interaction studies Clinical studies and model-guided methods Proton pump inhibitors: Based on the concomitant use of proton pump inhibitors (lansoprazole, omeprazole, esomeprazole, pantoprazole, or rabeprazole), no clinically significant differences in the pharmacokinetics of steady-state inalipse were observed.

[0263] In vitro studies CYP450 enzymes: Enallix induces CYP3A and CYP2B6. Enallix is ​​a time-dependent CYP3A inhibitor. Enallix does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.

[0264] Transporter systems: Enallix is ​​a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but not of OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2K, OAT1, or OAT2. Enallix does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K.

[0265] 13. Non-clinical toxicology 13.1 Carcinogenicity, mutagenicity, and impaired fertility The carcinogenicity of inalice has not yet been studied.

[0266] Enallix is ​​not mutagenic in the bacterial reverse mutation (Ames) assay. Enallix is ​​chromosomally break-inducing in the in vitro human lymphocyte micronucleus assay. Enallix is ​​not genotoxic in the in vivo rat bone marrow micronucleus assay and does not induce DNA breaks in the liver comet assay.

[0267] Fertility studies of enoxacillin have not yet been conducted. In repeated-dose toxicity studies, rats and dogs were administered enoxacillin orally once daily for up to 3 months.

[0268] In male rats, dose-dependent atrophy of the prostate and seminal vesicles, as well as decreased organ weight of the prostate, seminal vesicles, epididymis, and testes, were observed at doses ≥ 1.5 mg / kg / day (based on AUC, ≥ 0.4 times the human exposure at the recommended dose of 9 mg / day). In male dogs, localized condensation of seminiferous tubule contents and multinucleated sperm cells in the testes, as well as epithelial degeneration / necrosis in the epididymis, were observed after 4 weeks of administration at doses ≥ 1.5 mg / kg / day (based on AUC, ≥ 2 times the human exposure at the recommended dose of 9 mg / day). A decrease in sperm count was observed after 3 months of administration at doses ≥ 1 mg / kg / day (based on AUC, ≥ 1.2 times the human exposure at the recommended dose of 9 mg / day). These findings were not observed in dogs after the recovery period.

[0269] In female rats, after administration at doses ≥ 3 mg / kg / day (based on AUC, ≥ 1.2 times the human exposure at the recommended dose of 9 mg / day) for up to 3 months, uterine and vaginal atrophy, reduced follicle count, and findings suggestive of estrous cycle disruption / alteration were observed. The findings in the uterus, vagina, and estrous cycle observed in the 4-week toxicity study were not observed after recovery. Recovery was not assessed in the 3-month rat study.

[0270] 13.2 Animal toxicology and / or pharmacology Lens degeneration was observed in rats after oral administration of 10 mg / kg / day enoxaparin (based on AUC, 6.3 times the human exposure at the recommended dose of 9 mg / day), characterized by lens fiber swelling, lens fiber separation, and / or subcapsular protein accumulation. In dogs, lens fiber swelling and lens cortical vacuolation were observed at oral enoxaparin doses of ≥ 0.3 mg / kg / day (based on AUC, ≥ 0.5 times the human exposure at the recommended dose) and ≥ 1 mg / kg / day (based on AUC, ≥ 1.2 times the human exposure at the recommended dose), respectively. Lens degeneration persisted in rats after a 4-week recovery period but was absent in dogs after a 12-week recovery period.

[0271] 14 Clinical Studies 14.1 Locally advanced or metastatic breast cancer INAVO120 INAVO120 (NCT04191499) was a randomized (1:1), double-blind, placebo-controlled trial evaluating the combination of ITOVEBI with palbociclib and fulvestrant in patients with endocrine resistance, PIK3CA Efficacy was demonstrated in adult patients with HER2-mutant, HR-positive, HER2-negative (defined as IHC 0 or 1+, or IHC 2+ / ISH-) locally advanced or metastatic breast cancer whose disease progressed during or within 12 months of completing adjuvant endocrine therapy, and who had not previously received systemic therapy for locally advanced or metastatic disease. Randomization was stratified based on the presence (yes or no) of visceral disease, endocrine resistance (primary or secondary), and geographic region (North America / Western Europe, Asia, other).

[0272] Primary endocrine resistance is defined as relapse during the first 2 years of adjuvant endocrine therapy (ET), and secondary endocrine resistance is defined as relapse at least 2 years after adjuvant ET or within 12 months after completion of adjuvant ET.

[0273] Patients' HbA1c levels are required. 1C <6% and fasting blood glucose <126 mg / dL. The study excluded patients with type 1 diabetes or type 2 diabetes who required continuous antihyperglycemic therapy at the start of treatment.

[0274] PIK3CA The mutation status is determined in the central laboratory using FoundationOne on plasma-derived circulating tumor DNA (ctDNA). ® The diagnosis was prospectively determined by a liquid CDx assay, or by a variety of validated polymerase chain reaction (PCR) or next-generation sequencing (NGS) assays on tumor tissue or plasma at a local laboratory. All patients were required to provide freshly collected pre-treatment blood and tumor tissue samples for testing. PIK3CA Central assessment and determination of mutation states.

[0275] Patients received either ITOVEBI 9 mg orally once daily (n=161) or placebo (n=164), combined with palbociclib 125 mg orally once daily for 21 consecutive days, followed by a 7-day break to constitute a 28-day cycle. Fulvestrant 500 mg was administered intramuscularly on days 1 and 15 of cycle 1, and then on day 1 of each 28-day cycle. Patients received treatment until disease progression or unacceptable toxicity occurred. Furthermore, all premenopausal / perimenopausal women and men received an LHRH agonist throughout the treatment.

[0276] Baseline demographic and disease characteristics were as follows: median age 54 years (range: 27–79 years); 98% female, of whom 39% were premenopausal / perimenopause; 59% White, 38% Asian, 2.5% unknown, 0.6% Black or African American; 6% Hispanic or Latino; and Eastern Cooperative Oncology Group (ECOG) performance status of 0 (63%) or 1 (36%). Tamoxifen (57%) and aromatase inhibitors (50%) were the most commonly used adjuvant endocrine therapies. 64% of patients were considered to have secondary endocrine resistance. 83% of patients had previously received chemotherapy (in neoadjuvant / adjuvant settings), and 1.2% had received CDK4 / 6 inhibitor therapy.

[0277] The primary efficacy outcome measure was progression-free survival (PFS) as assessed by the investigator (INV) according to the RECIST version 1.1 criteria for evaluating efficacy in solid tumors. Other efficacy outcome measures included overall survival (OS), objective response rate (ORR) as assessed by the INV, and duration of response (DOR) as assessed by the INV.

[0278] Treatment outcomes are summarized in Table 6 and Figure 12. The PFS results assessed by INV were supported by consistent results from the blinded independent central review (BICR). At the time of the PFS analysis, OS data were not yet mature, with a mortality rate of 30% in the total population.

[0279] Table 6: Efficacy outcomes of INAVO120 in patients with locally advanced or metastatic breast cancer 16 How to supply / store and handle ITOVEBI is available in the following specifications and packaging configurations: Store at 20°C to 25°C (68°F to 77°F), with allowable deviations between 15°C and 30°C (between 59°F and 86°F) [see USP Controlled Room Temperature].

[0280] 17. Patient Consultation Information Patients are advised to read the FDA-approved patient label (patient information).

[0281] High blood sugar Inform the patient that ITOVEBI may cause hyperglycemia and that fasting blood glucose levels need to be monitored regularly during treatment. Advise the patient to contact their healthcare provider immediately if they experience signs and symptoms of hyperglycemia, such as excessive thirst, more frequent urination, blurred vision, confusion, difficulty breathing, or increased appetite with weight loss. [See Warnings and Precautions] (5.1)] .

[0282] Stomatitis Inform the patient that ITOVEBI may cause stomatitis (which can be serious) and that they should notify their healthcare provider if they develop symptoms of stomatitis (such as painful redness, swelling, or ulcers in the mouth). [See Warnings and Notes] Item (5.2)] .

[0283] diarrhea Inform the patient that ITOVEBI may cause diarrhea (which can be severe), and that if diarrhea occurs while taking ITOVEBI, antidiarrheal treatment should be started, oral rehydration should be increased, and their healthcare provider should be notified. [See warnings and notes] Note (5.3) .

[0284] Embryo-fetal toxicity Inform pregnant women and women of reproductive potential of the potential risks to the fetus. Advise women to inform their healthcare provider of any known or suspected pregnancy. [See Warnings and Precautions (5.4) and Use in Specific Populations (8.1)] .

[0285] Women of reproductive potential are advised to use an effective non-hormonal contraceptive method during ITOVEBI treatment and for one week after the last dose. [See Use in Specific Populations (8.3)] .

[0286] Male patients whose female partners are of reproductive potential are advised to use effective contraception during ITOVEBI treatment and for one week after the last dose. [See Use in Specific Populations (8.3)] .

[0287] Please refer to the full prescribing information for palbociclib and fulvestrant for pregnancy and contraception information.

[0288] Breastfeeding Women are advised not to breastfeed during ITOVEBI treatment and for one week after the last dose. [See also] Use in specific populations (8.2) Please refer to the full prescribing information for palbociclib and fulvestrant for information on breastfeeding.

[0289] Infertility Inform women and men of reproductive potential that ITOVEBI may impair fertility. [See in specific populations] Use (8.3)] Please refer to the complete prescribing information for palbociclib and fulvestrant for infertility information.

[0290] Dosage Instruct patients to take ITOVEBI at approximately the same time each day. [See Dosage and Administration (2.3)] .

[0291] Instruct patients that if they miss a dose of ITOVEBI, they should take the missed dose as soon as possible within 9 hours. If more than 9 hours have passed, skip the missed dose and take the next dose at the scheduled time. [See Dosage and Administration (2.3)] .

[0292] Instruct the patient that if vomiting occurs after taking an ITOVEBI dose, do not take an additional dose that day. Resume the normal dosing schedule the following day. [See Dosage and Administration (2.3)] .

[0293] Example 4 Inarizoline-based therapy in PIK3CA-mutated advanced breast cancer Enallix is ​​a potent and selective PI3Kα inhibitor that promotes the degradation of mutated p110α. The combination of enallix with palbociclib and fulvestrant has shown synergistic activity in preclinical models and promising antitumor activity in early trials.

[0294] In a phase 3, randomized, double-blind trial, we observed 325 patients with... PIK3CA In patients with HER2-negative, hormone receptor-positive, locally advanced / metastatic breast cancer (HR+, HER2- LA / mBC) who relapsed during or within 12 months of completing adjuvant endocrine therapy, first-line enoxaparin (9 mg once daily) plus palbociclib plus fulvestrant was compared with placebo plus palbociclib plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival.

[0295] At a median follow-up of 21.3 months, the median progression-free survival was 15.0 months (95% confidence interval [CI], 11.3 to 20.5) in the enoxacillin group and 7.3 months (5.6 to 9.3) in the placebo group (hazard ratio 0.43; 95% CI, 0.32 to 0.59; P < 0.001). The objective response rate was 58.4% in the enoxacillin group and 25.0% in the placebo group. The incidence of selected grade 3-4 adverse events in the enoxacillin group compared with the placebo group was: neutropenia, 80.2% vs. 78.4%; hyperglycemia, 5.6% vs. 0%; stomatitis and mucosal inflammation, 5.6% vs. 0%; diarrhea, 3.7% vs. 0%. No grade 3-4 rash was observed. The rates of any study treatment discontinuation due to adverse events were 6.8% in the inalipse group and 0.6% in the placebo group.

[0296] Inari, segaparbocili, and fulvestrant significantly improved the condition of patients with PIK3CA Patients with mutations, HR+, HER2- LA / mBC had progression-free survival and a low discontinuation rate associated with adverse events.

[0297] introduce Activated PIK3CA Mutations are frequent (approximately 35-40%) in hormone receptor-positive breast cancer (HR+ BC). 1-4It is a poor prognostic factor in advanced breast cancer and a predictive biomarker for response to phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitors. 1,3,5-7 Clinical trials have established regimens targeting key oncogenic drivers of HR+ BC, including combinations of endocrine therapy and cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors. 8-10 Or in combination with PI3K / protein kinase B (AKT) / mammalian target of rapamycin (mTOR) inhibitors; however, treatment resistance remains a major challenge in clinical practice. 11-13 The three key oncogenic pathways driving HR+ locally advanced / metastatic BC (LA / mBC) (estrogen receptor [ER], CDK4 / 6, PI3K) are highly interconnected and have complex feedback mechanisms that may drive adaptation / resistance. 14 There is a need for an effective treatment regimen that has an acceptable level of safety and can collectively target all three signaling pathways. Preclinical studies have shown that by... PIK3CA In mutant xenograft models, simultaneous blocking of the ER, CDK4 / 6, and PI3K pathways can achieve significant synergistic effects by enhancing response and preventing / delaying resistance. 15-17 However, previous attempts to use this method in clinical practice have not been successful, largely due to the side effects of the treatment. 18-20 Inarise is the p110 catalytic subunit α isoform (p110α; derived from) the PI3K complex. PIK3CA It is a highly effective and selective inhibitor of (encoding) p110α, which also promotes the degradation of mutant p110α. Previous PI3K inhibitors have been toxic and poorly tolerated when combined with standard-of-care agents; 11,21 Enalix's selective enhancement of p110α and degradation of mutant p110α may lead to a wider therapeutic window, enabling drug combination and sustained pathway inhibition. 17,22,23 A first-in-human Phase 1 study (NCT03006172) demonstrated that inalipse can be combined with palbociclib and fulvestrant at the maximum single dose of each drug without drug-drug interactions, with acceptable tolerability, and... PIK3CA It exhibits promising preliminary antitumor activity in mutated, HR+, and HER2-negative (HER2–) LA / mBC. 24 Preclinical and clinical data have demonstrated that, PIK3CA In breast cancer patients with mutations, HR+, and HER2-, the presence of a wide range of mutations occurs in major functional domains (i.e., helices, kinases, C2, etc.). PIK3CATumors with hotspot mutations are sensitive to inalipse alone or in combination with standard therapy. 17,25,26 INAVO120 (NCT04191499) is a phase 3, randomized, double-blind, placebo-controlled study in patients with... PIK3CA Patients with mutations, HR+, HER2– LA / mBC, and disease relapse within 12 months of completion of adjuvant endocrine therapy were evaluated for first-line inalaxise or placebo plus palbociclili plus fulvestrant; the trial enriched patients with clinicopathological features associated with poor prognosis.

[0298] method patient The study included premenopausal, perimenopausal, and postmenopausal women, as well as men, who had... PIK3CA Mutation, HR+, HER2– LA / mBC, disease relapse / progression within 12 months during or after adjuvant endocrine therapy (with) New Patients with metastatic breast cancer were excluded), fasting blood glucose <126 mg / dL, HbA1c 1C <6.0%, and have measurable disease as determined by the Remedial Evaluation Criteria for Solid Tumors (RECIST) v1.1. 27 PIK3CA A positive mutation result is determined by local testing of tumor tissue or circulating tumor DNA (ctDNA) using appropriately validated polymerase chain reaction or next-generation sequencing (NGS) assays in a laboratory that has received Clinical Laboratory Improvement Amendments or equivalent accreditation, or by testing ctDNA at a sponsor-designated central laboratory. Central ctDNA testing primarily utilizes FoundationOne. ® The Liquid CDx (F1LCDx) NGS assay was performed by Foundation Medicine, Inc., Cambridge, Massachusetts, USA; in China, the central ctDNA assay was performed by the PredicineCARE NGS assay (Shanghai, China).

[0299] Trial design and treatment Patients were randomized 1:1 using a replacement block designation to receive either enallixine (9 mg orally once daily [PO QD] from day 1 to day 28 of each 28-day cycle) or placebo (PO QD) in combination with palbociclib (125 mg PO QD from day 1 to day 21 of each 28-day cycle) plus fulvestrant (500 mg intramuscularly on days 1 and 15 of cycle 1, and approximately every 28 days thereafter). Premenopausal and perimenopausal women, as well as men, received hormone suppression via a luteinizing hormone-releasing hormone agonist during the trial treatment period. Treatment continued until disease progression / unacceptable toxicity / withdrawal of consent / death. Dosage modifications to enallixine and palbociclib are described in the protocol; dose reduction of fulvestrant is not permitted. Patients who discontinued any investigational drug due to intolerance were able to continue receiving other investigational drugs.

[0300] Randomization stratification factors were visceral disease (yes vs. no), endocrine resistance (primary vs. secondary), and region (North America / Western Europe vs. Asia vs. other). Primary endocrine resistance was defined as relapse during the first 2 years of adjuvant endocrine therapy; secondary endocrine resistance was defined as relapse after at least 2 years of adjuvant endocrine therapy or within 12 months of completing adjuvant endocrine therapy. 28 end The primary endpoint was investigator-assessed progression-free survival (time from randomization to the first occurrence of disease progression or death from any cause according to RECIST v1.1, whichever comes first). Patients without disease progression or death were censored at the last oncology assessment (or at randomization if no oncology assessment was performed after baseline visit). Secondary endpoints included overall survival; investigator-assessed confirmed objective response rate, best overall response, clinical benefit rate, and duration of response; and patient-reported outcomes. Safety, tolerability, and pharmacokinetics were also assessed.

[0301] The severity of adverse events is determined according to the National Cancer Institute’s Common Terminology Standard for Adverse Events, version 5.0. 29 The selected adverse events were defined based on the known safety features of Inalise and the adverse events of particular concern as defined by the program, and were assessed using grouping terminology.

[0302] Statistical analysis The INAVO120 assay was designed to detect a hazard ratio of 0.65 for progression-free survival (PFS) between inaglise and placebo using a two-tailed log-rank test at a significance level of 0.05, equivalent to a median PFS increase of 5.9 months. The primary analysis was planned after ~194 events (85% efficacy). Hazard ratios and corresponding 95% confidence intervals (CIs) were estimated using a stratified Cox proportional hazards model. Median PFS for each group was estimated using the Kaplan-Meier method, and the corresponding 95% CIs were constructed using the Brookmeyer-Crowley method. Subgroup analyses of PFS based on baseline characteristics were pre-specified. Stratified tests were performed on overall survival if the difference in PFS was statistically significant. Interim analyses (pre-specified boundaries, P < 0.0098) were planned during the primary PFS analysis, and the final analysis was planned after ~153 deaths.

[0303] Efficacy endpoint analyses were performed in the full analysis set (all randomized patients, regardless of whether they received the assigned study treatment). Duration of response was assessed in all randomized patients with objective responses. Safety analyses were performed in all patients who received ≥1 dose of any investigational drug (safety analysis set); participants were analyzed based on the treatment received.

[0304] Secondary efficacy endpoint analysis was performed using Type I error control.

[0305] result patient Between January 29, 2020, and September 14, 2023, 325 patients were enrolled. The majority of patients had tumors... PIK3CA Mutation status was determined by ctDNA-based detection. The median follow-up time was 21.3 months in the inalice group and 21.5 months in the placebo group (data cutoff: September 29, 2023).

[0306] Baseline characteristics were well balanced between the two groups (Table B1); median age was 54.0 years; 60.0% of patients were postmenopausal. The overall disease burden was high: 51.4% of patients had metastases in ≥ 3 organs; 80.0% had visceral disease; and 51.7% had liver metastases. Most patients had previously received (neo)adjuvant chemotherapy (82.8%), had not previously received CDK4 / 6 inhibitors (98.8%), and 47.7% had previously received only (neo)adjuvant tamoxifen. The distribution of relevant risk factors was well balanced, but Black or African American patients were underrepresented.

[0307] Table B1. Patient Demographics and Baseline Characteristics (Full Analysis Set) "Internal organs" (yes / no) refers to involvement of the lungs, liver, brain, pleura, and peritoneum.

[0308] † Patients with an evaluable skeletal-only disease are ineligible; patients with skeletal-only and at least one measurable soft tissue component are eligible according to RECIST 1.1.

[0309] ‡ According to the ASCO CAP guidelines, it is defined as ≥ 1%.

[0310] Other: Three patients (1.9%) were in the inalice group and six patients (3.7%) were in the placebo group.

[0311] Endocrine resistance is defined according to the 4th edition of the ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer. Primary resistance: Recurrence during the first 2 years of adjuvant endocrine therapy. Secondary resistance: Recurrence after at least 2 years of adjuvant endocrine therapy or within 12 months of completion of adjuvant endocrine therapy.

[0312] ASCO stands for American Society of Clinical Oncology, CAP stands for College of American Pathologists, ECOG PS stands for Eastern Cooperative Oncology Performance Status, ER stands for estrogen receptor, ESMO stands for European Society for Medical Oncology, ESO stands for European Academy of Oncology, PgR stands for progesterone receptor, and RECIST stands for criteria for evaluating the efficacy of treatment in solid tumors.

[0313] treat In the safety analysis set, patients in the enoxacillin group received a median of 9.2 months of enoxacillin, 9.1 months of palbociclib, and 8.6 months of fulvestrant; the median relative dose strengths were 95.8%, 87.3%, and 100.0%, respectively. Patients in the placebo group received a median of 5.6 months of placebo, 5.6 months of palbociclib, and 5.6 months of fulvestrant; the median relative dose strength for palbociclib was 88.4%, and for fulvestrant it was 100.0%.

[0314] efficacy In the full analysis set (n=161 in the quinalixe group and n=164 in the placebo group), the median progression-free survival was 15.0 months in the quinalixe group and 7.3 months in the placebo group (stratified hazard ratio 0.43; 95% CI, 0.32 to 0.59; P<0.001) (Figure 13). The event-free rates of the hallmark progression-free survival at 6, 12, and 18 months were 82.9%, 55.9%, and 46.2% in the quinalixe group, and 55.9%, 32.6%, and 21.1% in the placebo group, respectively. Subgroup analysis of progression-free survival revealed a generally consistent effect across key subgroups, including patients with and without visceral disease and liver metastases, although some subsets had smaller numbers of participants (Figure 14). In addition, progression-free survival was assessed by blinded independent central review as a sensitivity analysis; the results were consistent with the investigator-assessed progression-free survival (stratified hazard ratio, 0.50; 95% CI, 0.36 to 0.68; P<0.001).

[0315] In the interim overall survival analysis, the event-free rates of the hallmark overall survival at 6, 12, and 18 months were 97.3%, 85.9%, and 73.7% in the icoglitazone group, and 89.9%, 74.9%, and 67.5% in the placebo group, respectively. The stratified hazard ratio was 0.64 (95% CI, 0.43 to 0.97; P = 0.0338, which did not cross the predefined significance boundary [P < 0.0098]) (Figure 15).

[0316] The response rates in the inalipse group and the placebo group were 58.4% and 25.0%, respectively (Δ33.4%; 95% CI, 23.3 to 43.5); the median duration of response was 18.4 months and 9.6 months, respectively (hazard ratio 0.57; 95% CI, 0.33 to 0.99) (Figures 16 and 17).

[0317] Security In the safety analysis set (n=162 per group), the number of patients with ≥1 adverse event was 98.8% in the icoplanin group and 100% in the placebo group. Selected adverse events of any grade occurring in ≥20% of patients in either group were neutropenia (88.9% in the icoplanin group and 90.7% in the placebo group), stomatitis / mucosal inflammation (51.2% and 26.5%), hyperglycemia (58.6% and 8.6%), diarrhea (48.1% and 16.0%), and rash (25.3% and 17.3%) (Table B2). Febrile neutropenia was recorded in 2.5% and 0.6%, respectively. Based on body mass index (BMI), BMI ≥ 30 kg / m² was considered normal. 2 The incidence of hyperglycemia was 65.5%, and the BMI was <30 kg / m². 2 It is 56.8%.

[0318] Table B2. Most common adverse events of any grade (≥ 20%) in any treatment group (safety analysis set).

[0319] In the inalipase group and the placebo group, grade 3-4 adverse events were reported in 88.3% and 82.1% of cases, respectively. The reporting rates for grade 3-4 neutropenia were 80.2% and 78.4%, respectively; stomatitis / mucosal inflammation were 5.6% and 0%, respectively; hyperglycemia was 5.6% and 0%, respectively; and diarrhea was 3.7% and 0%, respectively. No grade 3-4 rash was reported.

[0320] In the inalipse group and the placebo group, the proportion of patients experiencing serious adverse events was 24.1% vs. 10.5%.

[0321] Grade 5 (fatal) adverse events were reported in 3.7% of patients in the inalipse group and 1.2% in the placebo group. In the inalipse group, these were acute coronary syndrome, COVID-19, cerebral hemorrhage, cerebrovascular accident, gastrointestinal bleeding, and death. In the placebo group, these were cardiac arrest and COVID-19 pneumonia. In both groups, these events were single occurrences and none were considered by the investigators to be related to the study treatment.

[0322] Adverse events led to discontinuation of any treatment in 6.8% of patients in the enoxacillin group (6.2% for enoxacillin, 4.9% for palbociclib, and 3.1% for fulvestrant), compared to 0.6% in the placebo group (placebo only; no patients discontinued palbociclib / fulvestrant due to adverse events). Adverse events leading to dose reductions in enoxacillin and placebo occurred in 14.2% and 3.1% of patients, respectively. Hyperglycemia (2.5%) was the only adverse event leading to dose reduction in enoxacillin, occurring in ≥ 2% of patients.

[0323] discuss INAVO120 met its primary endpoint, demonstrating efficacy in patients with PIK3CA In patients with HER2-mutant, HR+, HER2-LA / mBC disease who relapsed upon completion of adjuvant endocrine therapy or within 12 months thereafter, the addition of inalipate to palbociclib and fulvestrant resulted in significantly longer progression-free survival compared to placebo, palbociclib, and fulvestrant. The benefit of inalipate was generally observed in all key pre-specified clinical subgroups and sensitivity analyses and was supported by secondary endpoints, demonstrating meaningful improvements in response rate and duration. Overall survival analysis showed a numerical trend favorable to the inalipate group at interim analysis, and further follow-up is ongoing. Importantly, the safety profile of inalipate plus palbociclib and fulvestrant was consistent with that of the individual drugs. 11,24-26,30-34 Furthermore, the rate of treatment discontinuation due to adverse events is low.

[0324] The patient population enrolled in INAVO120 was enriched with adverse prognostic factors. INAVO120 enrolled patients with endocrine resistance and measurable disease, resulting in a high proportion of patients with a greater disease burden, including ≥3 organ involvement, visceral disease (80.0%), and liver metastases (51.7%). Furthermore, a unique aspect of the INAVO120 study is that >90% of patients had their tumor PIK3CA mutation status determined by ctDNA-based detection. These worse prognostic characteristics in the INAVO120 population were reflected in the control group and highlighted the improvement due to the addition of enoxacillin. The criteria used to define endocrine resistance are established internationally based on consensus.28 Endocrine resistance is a continuous manifestation attributable to and described by multiple contributing mechanisms. Strong preclinical and early clinical data suggest that this enoxacillin-based combination may be effective in a broader population beyond endocrine-resistant diseases treated with endocrine therapy alone. 17,22-24 The substantial clinical benefit observed in INAVO120 can be attributed to the simultaneous blocking of the driver. PIK3CAThree key signaling pathways—the PI3K, ER, and CDK4 / 6 pathways—are involved in mutations, HR+, and HER2–LA / mBC, thus delaying and preventing the emergence of treatment resistance primarily driven by crosstalk between these pathways. Furthermore, the clinical benefit in the inalipse group was early and durable, as evidenced by the early separation of the Kaplan-Meier curve for progression-free survival at initial tumor assessment, which was maintained throughout follow-up. Additionally, the hallmark mortality rates at 6 months were 10.1% in the placebo group and 2.7% in the inalipse group, highlighting the importance of using this inalipse-based combination as first-line therapy for this patient population.

[0325] INAVO120 established that inalipe can be used in combination with CDK4 / 6 inhibitors and endocrine therapy at full doses of all single-agent therapy, with acceptable levels of safety and tolerability. Hyperglycemia was more frequent in the inalipe group and in individuals with a BMI ≥ 30 kg / m². 2 The incidence was slightly higher in patients with hyperglycemia; this can be attributed to hyperglycemia being a targeted toxicity associated with PI3K pathway inhibitors. Other adverse events commonly associated with PI3K inhibitors, namely diarrhea, stomatitis, and rash, were also more frequent in the inalipse group. However, these key selected adverse events were managed with supportive care and dose adjustments, which was reflected in all high-dose intensities of the monotherapy. Furthermore, the INAVO120 regimen allows for prophylactic use of metformin in patients at high risk of hyperglycemia, and based on the SWISH study, early use of dexamethasone mouthwash as treatment, followed by prophylaxis for stomatitis, is recommended. 35 Prophylactic use of dexamethasone mouthwash from the start of treatment may be appropriate in routine clinical practice, and this will be explored in future studies. Furthermore, grade 3-4 rash, grade 3-4 pneumonia, and colitis were not reported, while neutropenia (including high-grade events) was similar between the inalice and placebo groups, and febrile neutropenia was low in both groups.

[0326] Although treatment algorithms for HR+ LA / mBC have evolved with the approval of combinations targeting the PI3K / AKT / mTOR pathway, for carriers... PIK3CA For patients with mutated tumors, these are not currently the preferred first-line treatments. Apellixil (a PI3Kα inhibitor) and everolimus (an mTOR inhibitor) are recommended second-line and later-line treatments, partly due to their challenging safety and tolerability profiles. For example, the treatment discontinuation rates due to adverse events for the apellixil and everolimus combination are 25.0% and 19%, respectively. 11,13In the INAVO120 trial, the treatment discontinuation rate due to adverse events in the inarithione group was 6.8%. Cross-trial comparisons should be conducted with caution due to differences in trial design, patient population, and analysis and reporting. However, it is noteworthy that attempts to combine apelis or everolimus with CDK4 / 6 inhibitors and endocrine therapy have not been successful, primarily due to toxicity. 19,36 Recently, capascacitinib (an AKT inhibitor) was approved in combination with fulvestrant for the treatment of patients with ≥1 AKT infection. PIK3CA / AKT1 / PTEN Patients with altered HR+, HER2– LA / mBC who have experienced progression or relapse on endocrine-based regimens. 12 In CAPItello-291, the treatment discontinuation rate due to adverse events was 13.0% for capasetinib plus fulvestrant. 12 This phase 3 study showed that in patients with PIK3CA In patients with mutations, HR+, HER2–LA / mBC, the combination of a PI3Kα inhibitor (inalilex), a CDK4 / 6 inhibitor, and endocrine therapy (all at full dose) significantly improved median progression-free survival while maintaining a low toxicity-related treatment discontinuation rate. This combination may represent a new treatment option for these patients.

[0327] References 1.Anderson EJ, Mollon LE, Dean JL, et al. A systematic review of theprevalence and diagnostic workup of PIK3CA mutations in HR+ / HER2- metastatic breast cancer. Int J Breast Cancer 2020;2020:3759179. 2. Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase andantiestrogen resistance in breast cancer. J Clin Oncol 2011;29:4452-61.

[0328] 3. LoRusso PM. Inhibition of the PI3K / AKT / mTOR pathway in solid tumors. J Clin Oncol 2016;34:3803-15.

[0329] 4. Martínez-Sáez O, Chic N, Pascual T, et al. Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast Cancer Res 2020;22:45.

[0330] 5. Fillbrunn M, Signorovitch J, André F, et al. PIK3CA mutation status, progression and survival in advanced HR+ / HER2- breast cancer: a meta-analysis of published clinical trials. BMC cancer 2022;22:1002.

[0331] 6. Hanker AB, Sudhan DR, Arteaga CL. Overcoming endocrine resistance in breast cancer. Cancer Cell 2020;37:496-513.

[0332] 7. Zardavas D, Te Marvelde L, Milne RL, et al. Tumor PIK3CA Genotype and Prognosis in Early-Stage Breast Cancer: A Pooled Analysis of Individual Patient Data. J Clin Oncol 2018;36:981-90.

[0333] 8. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): Final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 2016;17:425-39。

[0334] 9. Slamon DJ, Neven P, Chia SKL, et al. Updated overall survival (OS) results from the phase III MONALEESA-3 trial of postmenopausal patients (pts) with HR+ / HER2- advanced breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB). J Clin Oncol 2021;39:Abstract 1001。

[0335] 10. Sledge GW, Jr., Toi M, Neven P, et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+ / HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 2017;35:2875-84。

[0336] 11. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med 2019;380:1929-40。

[0337] 12. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor–positive advanced breast cancer. N Engl J Med 2023;388:2058-70。

[0338] 13. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor–positive advanced breast cancer. N Eng J Med 2011;366:520-9。

[0339] 14. Presti D, Quaquarini E. The PI3K / AKT / mTOR and CDK4 / 6 pathways in endocrine resistant HR+ / HER2- metastatic breast cancer: biological mechanisms and new treatments. Cancers (Basel) 2019;11:1242。

[0340] 15. Herrera-Abreu MT, Palafox M, Asghar U, et al. Early adaptation and acquired resistance to CDK4 / 6 inhibition in estrogen receptor-positive breast cancer. Cancer Res 2016;76:2301-13。

[0341] 16. Vora SR, Juric D, Kim N, et al. CDK 4 / 6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer cell 2014;26:136-49。

[0342] 17. Song KW, Edgar KA, Hanan EJ, et al. RTK-dependent inducible degradation of mutant PI3Kα drives GDC-0077 (inavolisib) efficacy. Cancer Discov 2022;12:204-19.

[0343] 18. Juric D, Ismail-Khan R, Campone M, et al. Phase Ib / II study of ribociclib and alpelisib and letrozole in ER+, HER2– breast cancer: safety, preliminary efficacy and molecular analysis. Cancer Res 2016;76:Abstract P3-14-01.

[0344] 19. Tolaney SM, Im YH, Calvo E, et al. Phase Ib study of ribociclib plus fulvestrant and ribociclib plus fulvestrant plus PI3K inhibitor (alpelisib or buparlisib) for HR(+) advanced breast cancer. Clin Cancer Res 2021;27:418-28.

[0345] 20. Pascual J, Lim JSJ, Macpherson IR, et al. Triplet therapy with palbociclib, taselisib, and fulvestrant in PIK3CA-mutant breast cancer and doublet palbociclib and taselisib in pathway-mutant solid cancers. Cancer Discov 2021;11:92-107.

[0346] 21. Dent S, Cortés J, Im YH, et al. Phase III randomized study of taselisibor placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: the SANDPIPER trial. Ann Oncol 2021;32:197-207.

[0347] 22. Edgar K, Hong R, Song K et al. GDC-0077 is a selective PI3K alpha inhibitor with robust efficacy in PIK3CA mutant hormone-positive breastcancer models. Cancer Res 2020;80:Abstract P3-11-23 and related posters.

[0348] 23. Hanan EJ, Braun MG, Heald RA, et al. Discovery of GDC-0077(inavolisib), a highly selective inhibitor and degrader of mutant PI3Kα. J MedChem 2022;65:16589-621.

[0349] 24.Bedard PL, Jhaveri K, Cervantes A, et al. A phase I / Ib study evaluating GDC-0077 + palbociclib (palbo) + fulvestrant in patients (pts) with PIK3CA -mutant (mut), hormone receptor-positive / HER2-negative metastatic breastcancer (HR+ / HER2- mBC). Cancer Res 2021;81:Abstract PD1-02 and related poster display.

[0350] [ PubMed ] 25.Juric D、Kalinsky K、Oliveira M. A first-in-human phase Ia dosescaling study of GDC-0077, a p110a-selective and mutant-degrading PI3Kinhibitor, in patients with PIK3CA -mutant solid tumors.Cancer Res 2020;80:Abstract OT1-08-4

[0351] 26.Jhaveri K、Kalinsky K、Bedard P Activity A phase Ib dose escalationstudy evaluating the mutant selective PI3K-alpha inhibitor GDC-0077 (G) in combination with letrozole (L) with and without palbociclib (P) in patientswith PIK3CA-mutant HR+ / HER2- breast cancer.Cancer Res 2020;80:Abstract P1-19-46.

[0352] 27.Eisenhauer EA、Therasse P、Bogaerts J New response evaluationcriteria in solid tumors: revised RECIST guideline (version 1.1).Eur JCancer 2009;45:228-47.

[0353] 28.Cardoso F, Senkus E, and Costa A. 4th ESO-ESMO InternationalConsensus Guidelines for Advanced Breast Cancer (ABC 4)†.Ann Oncol 2018;29:1634-57.

[0354] 29. 不良事件通用术语标准(CTCAE)第5.0版。美国国立癌症研究所(NCI):癌症治疗与诊断司(DCTD),(https: / / ctep.cancer.gov / protocoldevelopment / electronic_applications / docs / CTCAE_v5_Quick_Reference_5x7.pdf.) 30. Oliveira M、Jhaveri K、Juric D等人,一项I / Ib期研究中的靶向安全性事件,该研究评估了GDC - 0077单药以及与内分泌治疗(ET)联合使用±哌柏西利(palbo)在 PIK3CA -突变(mut)、激素受体阳性 / 人表皮生长因子受体2阴性转移性乳腺癌(HR + / HER2 - mBC)患者中的情况(pts)。《癌症研究》2021年;81卷:摘要PS11 - 和相关海报展示。

[0355] 31. Bedard PL、Accordino MK、Cervantes A等人,在一项正在进行的1 / 1b期研究中,inavolisib(GDC - 0077)的长期安全性,该研究评估了单药治疗以及与哌柏西利(palbo)和 / 或内分泌治疗联合使用(联合用药)在 PIK3CA-mutated, hormone receptor-positive / HER2-negative(HR+ / HER2–) metastatic breast cancer (BC). J Clin Oncol, June 3–7, 2022. Abstract 1052;40:Abstract 1052.

[0356] 32. Kalinsky K, Juric D, Bedard PL, et al. A phase I / Ib study evaluating GDC-0077 plus fulvestrant in patients with PIK3CA -mutant, hormone receptor-positive / HER2-negative breast cancer. Cancer Res 2020;80:Abstract CT109 and related oral presentation.

[0357] 33. Juric D, Bedard PL, Cervantes A, et al. A phase I / Ib study of inavolisib (GDC-0077) in combination with fulvestrant in patients (pts) with PIK3CA -mutated hormone receptor-positive / HER2-negative (HR+ / HER2–) metastatic breast cancer. Cancer Res 2022;82:Abstract P5-17-05.

[0358] 34. Di Leo A, Jerusalem G, Petruzelka L, et al. Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial. J Natl Cancer Inst 2014;106:djt337.

[0359] 35.Rugo HS, Seneviratne L, Beck JT, et al. Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negativemetastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial. Lancet Oncol 2017;18:654-62.

[0360] 36.Bardia A, Hurvitz SA, DeMichele A, et al. Phase I / II trial of exemestane, ribociclib, and everolimus in women with HR + / HER2 – advanced breastcancer after progression on CDK4 / 6 inhibitors (TRINITI-1). Clin Cancer Res2021;27:4177-85.

[0361] Another embodiment Generally, any aspect or embodiment described herein from the perspective of a treatment method can also be defined from the perspective of compounds or combinations used to treat a specific condition and associated with any specific patient characteristic, such as a specific patient population. These compounds or combinations used for defined treatments associated with any specific patient characteristic also constitute a part of this invention.

[0362] Specific aspects of the invention are defined by the following numbered statements.

[0363] 1A. An assembly comprising: (i) Inalice; (ii) palbociclib; and (iii) Fluvestrant, For the treatment of patients with PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer, treatment includes administration of a combination therapy comprising the combination, wherein the combination therapy produces statistically significant and clinically meaningful improvement in patients compared to administration of palbociclib and fulvestrant alone to comparable patients.

[0364] 2A. A combination comprising: (i) Inalice; (ii) palbociclib; and (iii) Fluvestrant, This treatment is indicated for patients with PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer. The treatment comprises administering a combination therapy to the patient, wherein the combination therapy includes a dosing regimen comprising: a. Administer inalice during the first 28-day cycle (QD) from day 1 to day 28; b. Administer palbociclib via QD from day 1 to day 21 of the first 28-day cycle; and c. Administer fulvestrant on days 1 and 15 of the first 28-day cycle. Compared with the administration of palbociclib and fulvestrant alone to comparable patients, the combination therapy produced statistically significant and clinically meaningful improvements in patients.

[0365] 3A. A combination comprising: (i) Inalice; (ii) palbociclib; and (iii) Fluvestrant, This combination therapy is used to suppress tumor growth or produce / increase tumor regression in patients with PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer by administering the combination to them.

[0366] 4A. A combination comprising: (i) Inalice; (ii) palbociclib; and (iii) Fluvestrant, It is used to prevent or delay the development of resistance in patients to treatments containing palbociclib by administering combination therapy, which includes the combination of these components.

[0367] 5A. The combination used according to any one of 1A to 4A, wherein the combination therapy further comprises one or more additional 28-day cycles, which include: a. Administer inarise on days 1 through 28 of each additional 28-day cycle; b. Administer palbociclib from day 1 to day 21 of each additional 28-day cycle; and c. Administer fulvestrant on day 1 of each additional 28-day cycle.

[0368] 6A. The combination used according to any one of 1A to 5A, wherein inarise is administered in a dose of 9 mg.

[0369] 7A. The combination used according to 6A, wherein inarise is administered orally in a dose of 9 mg in tablet form.

[0370] 8A. The combination of any one of 1A to 7A, wherein palbociclib is administered orally in a dose of 125 mg in capsules or tablets.

[0371] 9A. The combination used according to any one of 1A to 8A, wherein fulvestrant is administered by intramuscular (IM) infusion at a dose of 500 mg.

[0372] 10A. The combination used according to any one of 1A to 9A, wherein the patient has locally advanced or metastatic breast cancer that is not suitable for curative therapy.

[0373] 11A. The combination used according to any one of 1A to 10A, wherein the breast cancer is endocrine resistant.

[0374] 12A. The combination used according to any one of 1A to 11A, wherein the patient has disease progression during adjuvant endocrine therapy or within 12 months of completing adjuvant endocrine therapy.

[0375] 13A. The combination used according to claim 12A, wherein the patient experiences disease progression during the first two years of adjuvant endocrine therapy.

[0376] 14A. The combination used as described in 12A or 13A, wherein the adjunctive endocrine therapy is the use of an aromatase inhibitor or tamoxifen.

[0377] 15A. The combination used according to 14A, wherein the adjunctive endocrine therapy is tamoxifen alone.

[0378] 16A. The combination used according to any one of 1A to 15A, wherein the patient has adequate blood and organ function within 14 days prior to the start of administration of the combination therapy.

[0379] 17A. The combination used according to any one of 1A to 16A, wherein the patient is not postmenopausal.

[0380] 18A. The combination used according to any one of 1A to 17A, wherein the patient has PIK3CA-mutated, hormone receptor-positive, and HER2-negative metastatic breast cancer.

[0381] 19A. The combination used according to any one of 1A to 18A, wherein the patient has PIK3CA mutation, estrogen receptor positive, progesterone receptor positive and HER2 negative locally advanced or metastatic breast cancer.

[0382] 20A. The combination used according to any one of 1A to 19A, wherein the patient is an adult.

[0383] 21A. The combination used according to any one of 1A to 20A, wherein the patient is less than 65 years old.

[0384] 22A. The combination used according to any one of 1A to 21A, wherein the breast cancer is detected by an FDA-approved test.

[0385] 23A. An assembly comprising: (i) Inalice; (ii) palbociclib; and (iii) Fluvestrant, This treatment is indicated for the treatment of adult patients with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer, including treatment that involves administering combination therapy to the patient during or after adjuvant endocrine therapy if recurrence occurs.

[0386] 24A. The combination used according to 23A, wherein breast cancer is detected by an FDA-approved test.

[0387] Many variations and other embodiments of the invention set forth herein will come to mind for those skilled in the art, taking advantage of the teachings presented in the foregoing description and the accompanying drawings. Therefore, it should be understood that the invention is not limited to the specific embodiments disclosed, and that variations and other embodiments are intended to be included within the scope of the appended claims. Although specific terminology is used herein, it is used only in a general and descriptive sense and not for limiting purposes.

Claims

1. A method for treating a patient with PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer, the method comprising administering a combination therapy to the patient, the combination therapy comprising: (i) Inalice; (ii) palbociclib; and (iii) Fluvestrant, The combination therapy produced statistically significant and clinically meaningful improvements in the patients compared to administration of palbociclib and fulvestrant alone to comparable patients.

2. A method for treating a patient with PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer, the method comprising administering a combination therapy to the patient, the combination therapy comprising a dosing regimen comprising: a. Administer inalice during the first 28-day cycle (QD) from day 1 to day 28; b. Administer palbociclib via QD from day 1 to day 21 of the first 28-day cycle; and c. Administer fulvestrant on days 1 and 15 of the first 28-day cycle. The combination therapy produced statistically significant and clinically meaningful improvements in the patients compared to administration of palbociclib and fulvestrant alone to comparable patients.

3. The method of claim 1 or 2, further comprising one or more additional 28-day cycles, said one or more additional 28-day cycles comprising: a. Administer inarise on days 1 through 28 of each additional 28-day cycle; b. Administer palbociclib from day 1 to day 21 of each additional 28-day cycle; and c. Administer fulvestrant on day 1 of each additional 28-day cycle.

4. The method according to any one of claims 1 to 3, wherein inarise is administered in an amount of 9 mg.

5. The method of claim 4, wherein inarise is administered orally in a dose of 9 mg in tablet form.

6. The method according to any one of claims 1 to 5, wherein palbociclib is administered orally in an amount of 125 mg in capsules or tablets.

7. The method according to any one of claims 1 to 6, wherein fulvestrant is administered via intramuscular (IM) infusion at a dose of 500 mg.

8. A method for inhibiting tumor growth or producing / increasing tumor regression in a patient with PIK3CA-mutated, hormone receptor-positive, and HER2-negative locally advanced or metastatic breast cancer, the method comprising administering a combination therapy to the patient according to any one of claims 1 to 7.

9. The method according to any one of claims 1 to 8, wherein the patient has locally advanced or metastatic breast cancer that is not suitable for curative treatment.

10. The method according to any one of claims 1 to 9, wherein the breast cancer is endocrine resistant.

11. The method according to any one of claims 1 to 10, wherein the patient has disease progression during adjuvant endocrine therapy or within 12 months of completion of adjuvant endocrine therapy.

12. The method of claim 11, wherein the patient has disease progression during the first two years of adjuvant endocrine therapy.

13. The method of claim 11 or 12, wherein the adjuvant endocrine therapy is the use of an aromatase inhibitor or tamoxifen.

14. The method of claim 13, wherein the adjuvant endocrine therapy is tamoxifen only.

15. The method according to any one of claims 1 to 14, wherein the patient has adequate blood and organ function within 14 days prior to the start of treatment.

16. The method according to any one of claims 1 to 15, wherein the patient is not postmenopausal.

17. The method according to any one of claims 1 to 16, wherein the patient has metastatic breast cancer with a PIK3CA mutation, hormone receptor positivity, and HER2 negativity.

18. The method according to any one of claims 1 to 17, wherein the patient has locally advanced or metastatic breast cancer with a PIK3CA mutation, estrogen receptor positivity, progesterone receptor positivity, and HER2 negativity.

19. The method according to any one of claims 1 to 18, wherein the patient is an adult.

20. The method of any one of claims 1 to 19, wherein the breast cancer is detected by an FDA-approved test.

21. A method for preventing or delaying the development of resistance in breast cancer to a therapy containing palbociclib, the method comprising administering a combination therapy comprising enoxaparin, palbociclib, and fulvestrant according to any one of claims 1 to 20.

22. A method for treating an adult patient with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer, the method comprising administering to the patient a combination therapy comprising inalipse, palbociclib, and fulvestrant during or after adjuvant endocrine therapy and following recurrence.

23. The method of claim 22, wherein the breast cancer is detected by an FDA-approved test.

24. A combination therapy comprising inaricept, palbociclib, and fulvestrant for the treatment of adults with locally advanced or metastatic breast cancer that is endocrine-resistant, PIK3CA-mutated, hormone receptor (HR) positive, and human epidermal growth factor receptor 2 (HER2) negative, as detected by an FDA-approved test, after recurrence during or following adjuvant endocrine therapy.

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