Combination therapy for treating her2 cancer

Abstract

Combination therapy comprising inalipase and a fixed-dose combination (PH FDC SC) of pertuzumab and trastuzumab for subcutaneous injection is provided for the treatment of HER2-positive cancer; and a method for treating PIK3CA-mutated HER2-positive (HER2+) locally advanced or metastatic breast cancer, the method comprising administering a therapeutically effective amount of inalipase and PH FDC SC.

Description

Cross-reference to related applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 606,488, filed December 5, 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] This invention generally relates to the treatment of patients with PIK3CA-mutated HER2-positive locally advanced or metastatic breast cancer by administering inalipsa in combination with a fixed-dose combination (PH FDC SC) of pertuzumab and trastuzumab for subcutaneous injection. 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 have some form of molecular aberration in the PI3K / AKT / mTOR pathway. Activation of mutations in PIK3CA (encoding the p110α subunit of PI3K) is very common in breast cancer and solid tumors.

[0005] Although PI3Kα inhibitors have been approved or are in clinical development for the treatment of patients with hormone receptor (HR) positive, HER2 negative, locally advanced or metastatic breast cancer carrying PIK3CA mutations, active agents are still needed to treat HER2 positive cancers. Summary of the Invention

[0006] This disclosure provides a combination therapy for the treatment of breast cancer that overexpresses HER2, comprising a combination of inalipase with a fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC or Hergacon®).

[0007] One aspect of this disclosure provides a combination therapy for treating PIK3CA-mutated HER2-positive (HER2+) breast cancer, the combination therapy comprising inalipse and PH FDC SC.

[0008] This disclosure further provides a method for treating locally advanced or metastatic PIK3CA-mutated (or PIK3CA mutant) HER2-positive breast cancer, the method comprising administering a therapeutically effective amount of inalipse and PH FDC SC to a patient in need.

[0009] In some embodiments, the patient has locally advanced or metastatic PIK3CA-mutated HER2+ breast cancer. In some embodiments, the patient has a left ventricular ejection fraction (LVEF) of 50% or greater. In some embodiments, the patient is female.

[0010] In one aspect, a method is provided for treating HER2-positive breast cancer in a patient with locally advanced or metastatic PIK3CA-mutated HER2-positive breast cancer, the method comprising administering a combination therapy comprising enoxacillin and PHFDC SC to the patient. In some embodiments, the combination therapy is administered over a 21-day cycle.

[0011] In one aspect, a method is provided for treating a patient with HER2-positive breast cancer who has locally advanced or metastatic PIK3CA-mutated breast cancer, the method comprising administering to the patient a combination therapy comprising a dosing regimen including: a. Administer inolic acid on days 1 through 21 of the first 21-day cycle (QD); and b. Administer PH FDC SC on day 1 of the first 21-day cycle.

[0012] The method may further include one or more additional 21-day cycles comprising the following: a. Administer inarise on days 1 through 21 of each additional 21-day cycle; and b. Administer PH FDC SC on day 1 of each additional 21-day cycle.

[0013] In some embodiments, prior to administration of the combination therapy comprising enoxacillin and PH FDC SC, the patient has received induction therapy, which includes administration of pertuzumab and trastuzumab (Perjeta and Herceptin, or PH) and taxane-based chemotherapy. In some embodiments, induction therapy includes administration of PH FDC SC and taxane-based chemotherapy (e.g., paclitaxel). Other examples of taxane-based chemotherapy include docetaxel and nab-paclitaxel. In some embodiments, induction therapy includes a dosing regimen comprising four (4) to eight (8) 21-day cycles: (a) administration of PH FDC SC on day 1 of each 21-day cycle; and (b) administration of paclitaxel on days 1, 8, and 15 of each 21-day cycle. In some embodiments, the induction therapy includes a dosing regimen comprising four (4) to eight (8) 21-day cycles of: (a) administration of PH FDC SC on day 1 of each 21-day cycle; and (b) administration of taxane-based chemotherapy according to SoC (e.g., administration of docetaxel or nano-albumin-bound paclitaxel on day 1 of each 21-day cycle).

[0014] In some of these embodiments, enoxacillin is administered in a dose of 9 mg (e.g., in the form of an oral tablet). In some of these embodiments, PH FDC SC comprises 600 mg pertuzumab, 600 mg trastuzumab, and rHuPH20 SC.

[0015] In some embodiments, the patient has hormone receptor-positive (HR+) locally advanced or metastatic PIK3CA-mutated HER2-positive breast cancer, and the method further includes administering endocrine therapy (e.g., fulvestrant or aromatase inhibitor) to the patient.

[0016] In some embodiments, the method further includes administering fulvestrant to the patient, for example, by intramuscular (IM) infusion of 500 mg approximately every four weeks.

[0017] In some embodiments, the method further includes administering an aromatase inhibitor (e.g., anastrozole, letrozole, or exemestane) to the patient.

[0018] Also provided are combinations for the treatment of locally advanced or metastatic PIK3CA-mutated (or PIK3CA mutant) HER2-positive breast cancer, wherein the combination comprises inalipse or a pharmaceutically acceptable salt thereof and PH FDCSC (Hergacon).

[0019] It also provides the use of the combination in the manufacture of a medicament for the treatment of locally advanced or metastatic PIK3CA-mutated (or PIK3CA mutant) HER2-positive breast cancer, wherein the combination comprises inalipse or a pharmaceutically acceptable salt thereof and PH FDC SC (Hergacon).

[0020] In another aspect, a method is provided for inhibiting tumor growth or producing / increasing tumor regression in a patient with locally advanced or metastatic PIK3CA-mutated (or PIK3CA mutant) HER2-positive breast cancer, the method comprising administering combination therapy to the patient according to the methods detailed herein.

[0021] On the other hand, a combination is provided for use in patients with HER2-positive breast cancer who have locally advanced or metastatic PIK3CA mutations to inhibit tumor growth or produce / increase tumor regression.

[0022] On the other hand, the use of the combination or use detailed herein is provided in the manufacture of a medicine for inhibiting tumor growth or producing / increasing tumor regression in patients with locally advanced or metastatic PIK3CA-mutated HER2-positive breast cancer.

[0023] A further method is provided for preventing or delaying the development of resistance in tumors (e.g., breast cancer) to therapies containing HER2-targeted therapies, the method comprising administering a combination therapy comprising inalipse and PH FDC SC (Hergacon). In some embodiments, the combination therapy is administered according to any of the methods detailed herein.

[0024] Also provided are combinations for preventing or delaying the development of resistance in tumors (e.g., breast cancer) to therapies containing HER2-targeted therapies, wherein said combination comprises inalipse and PH FDC SC (Hergacon). In some embodiments, said combination is administered according to any use as detailed herein.

[0025] Also provided is the use of the combination in the manufacture of a medicament for preventing or delaying the development of resistance in tumors (e.g., breast cancer) to therapies containing HER2-targeted therapies, wherein said composition comprises inalipse and PH FDC SC (Hergacon). In some embodiments, the combination is administered according to any use as detailed herein. Attached Figure Description

[0026] Figure 1 shows the study design of a phase III study (INAVO122) in patients with HER2-positive advanced breast cancer with PIK3CA mutations who underwent induction with pertuzumab + trastuzumab + taxane followed by maintenance therapy with either inalipase or placebo + pertuzumab + trastuzumab. Detailed Implementation

[0027] 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.

[0028] 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, relief of detectable or undetectable symptoms, 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 extended 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.

[0029] 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 some extent slow down and preferably stop) the infiltration of cancer cells into surrounding organs; inhibit (i.e., to some extent slow down and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more symptoms associated with cancer to some extent. To some extent, the drug can stop the growth and / or kill existing cancer cells, and it can inhibit cell growth and / or be cytotoxic. For cancer treatment, efficacy can be measured, for example, by assessing time to progression (TTP) and / or determining the response rate (RR).

[0030] "Time to Progression" or "TTP" refers to the time from randomization to objective tumor progression.

[0031] 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.

[0032] "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.

[0033] "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.

[0034] "Clinical benefit rate" or "CBR" refers to the proportion of patients who achieve complete remission, partial remission, and / or stable disease for at least 24 weeks as determined by RECIST v1.1.

[0035] "Total survival" or "OS" refers to the time from enrollment to death from any cause.

[0036] "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.

[0037] "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).

[0038] "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.

[0039] "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.

[0040] "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.

[0041] "Complete remission" or "CR" refers to the disappearance of all target and non-target lesions and (if applicable) the normalization of tumor marker levels.

[0042] "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 reduction of ≥30% 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.

[0043] "Disease progression" 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.

[0044] "Disease stable" or "SD" means that the tumor has neither shrunk sufficiently to meet the requirements of CR or PR, nor has it grown sufficiently to meet the requirements of PrD.

[0045] "Application period" or "cycle" refers to a period of time that includes the application of one or more of the pharmaceutical agents described herein, and optionally a period of time that does not include 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 period of 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. In one embodiment, a cycle does not include any rest period.

[0046] "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.

[0047] "Once a day" (QD) means applying the compound once a day.

[0048] Graded adverse events refer to the severity level determined by NCI CTCAE. In one implementation scheme, adverse events are graded according to the table below.

[0049] The term "detection" includes any detection method, including direct and indirect detection.

[0050] 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.

[0051] 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 prediction method of the present invention can be clinically used to make treatment decisions. The prediction 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.

[0052] 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.

[0053] "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 tumor cell number; (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 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) reduced mortality at a given time point after treatment.

[0054] "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.

[0055] 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).

[0056] "Chemotherapy agents" are biological (macromolecule) or chemical (small molecule) compounds that can be used to treat cancer, regardless of their mechanism of action.

[0057] 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.

[0058] As used herein, the phrase "pharmaceutical salt" refers to the 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 bis(hydroxynaphthyl)ate (i.e., 1,1'-methylene-di-(2-hydroxy-3-naphthylcarbamate)). Pharmaceutical salts may involve inclusion complexes of another molecule, such as acetate ions, succinate ions, or other counterions. Counterions can be any organic or inorganic portion that stabilizes the charge on the parent compound. Furthermore, a medicinal salt may have more than one charged atom in its structure. An example where multiple charged atoms are part of a medicinal salt may have multiple counterions. Therefore, a medicinal salt may have one or more charged atoms and / or one or more counterions.

[0059] The desired pharmaceutical 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 drug 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 J. of Pharmaceutics (1986) 33 201 217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; Remington's Pharmaceutical Sciences, 18 th ed., (1995) Mack Publishing Co., Easton PA; and in The OrangeBook (Food & Drug Administration, Washington, DC on their website). These publicly available contents are incorporated herein by reference.

[0060] 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.

[0061] As used herein, the term "synergistic" refers to a therapeutic combination that is more effective than the additive effect of two or more individual 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 a 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 standard procedures used by Chou and Talalay in "New Avenues in Developmental Cancer Chemotherapy," Academic Press, 1987, Chapter 2, to quantify synergistic, additive, and antagonistic effects in anticancer agents. A combination index value less than 0.8 indicates a synergistic effect, a value greater than 1.2 indicates an antagonistic effect, and a value between 0.8 and 1.2 indicates an additive effect. 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 of using the compounds alone. Synergistic effects are achieved 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) via some other protocol. When delivered in an alternating therapy, synergistic effects are achieved if the compounds are administered or delivered sequentially, for example, by injection in separate syringes or in separate pill or tablet form. Generally, in alternating therapies, the sequence is the sequential administration of each active ingredient at an effective dose, while in combination therapies, two or more active ingredients at effective doses are administered together. Combination effects were assessed using the BLISS independence model and the highest single-agent (HSA) model (Lehár et al. 2007, Molecular Systems Biology 3:80). The BLISS score quantifies the enhancement of the single agents, with a BLISS score >0 indicating a greater than simple summation. An HSA score > 0 indicates that the combined effect is greater than the maximum response of a single reagent at the corresponding concentration.

[0062] As used herein, unless otherwise stated, “induction therapy” means first-line treatment of advanced breast cancer (ABC) with paclitaxel (e.g., paclitaxel, docetaxel, or nano-albumin-bound paclitaxel) plus pertuzumab and trastuzumab (PH) or PH FDC SC (Hergacon) in accordance with standard of care (SoC), and “maintenance therapy” means subsequent treatment in participants who have not experienced disease progression after induction therapy with inalipsa or placebo in combination with PH FDC SC (Hergacon).

[0063] clinical compounds Inalice: Enalix is ​​a potent, orally bioavailable, clinical-stage selective inhibitor of class I PI3K α isoform (PI3Kα), with >300-fold reduced efficacy against other class I PI3K β, PI3K δ, and PI3K γ isoforms, and increased efficacy in tumor cells carrying mutant PI3K compared to wild-type (WT) PI3K cells (Braun, M. et al., “Discovery of GDC-0077: A highly selective inhibitor of PI3K-alpha that induces degradation of mutant-p110alpha protein”, Abstracts of Papers, 254th ACS National Meeting & Exposition, Washington, DC, USA, August 20-24, 2017, MEDI-22; Garland, K. et al., “Discovery of novel class of alpha selective PI3K inhibitors”, Abstracts of Papers, 254th). ACSNational Meeting&Exposition, Washington, DC, USA, August 20-24, 2017, MEDI-103; 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" 2017 San Antonio Breast CancerSymposium, December 5-9, 2017 Japan, San Antonio, TX, Abstract PublicationNumber: PD4-14; Edgar, K."Preclinical characterization of GDC-0077, a specific PI3K alpha inhibitor in early clinical development" by et al., Cancer Research 77 (Supplement 13): Abstract 156 (July 2017).

[0064] Inarise, CAS Registry No. 2060571-02-8, Genentech, US 9650393; named (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazolidin-9-yl)amino)propionamide, has the following structure: .

[0065] Inarise is also known as GDC-0077, RG6114, RO7113755, or by the 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.

[0066] 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 demonstrated that enallix specifically degrades mutant p110α, inhibits the proliferation of PIK3CA mutant breast cancer cell lines and induces apoptosis, suppresses tumor growth in human breast cancer xenograft models carrying PIK3CA mutations, and reduces downstream PI3K pathway markers, including the phosphorylated form of protein kinase B (pAKT), PRAS40 phosphorylated at threonine 246 (pPRAS40), and S6RP phosphorylated at serine 235 / 236 (pS6RP).

[0067] Trastuzumab: Trastuzumab (CAS 180288-69-1, Herceptin®, huMAb4D5-8, rhuMAb HER2, Genentech) is a recombinant DNA-derived IgG1κ monoclonal antibody, a humanized form of a mouse anti-HER2 antibody (4D5), which binds selectively to the extracellular domain of HER2 with high affinity (Kd = 5 nM) in cell-based assays (US 5677171; US ​​5821337; US 6054297; US 6165464; US 6339142; US 6407213; US6639055; US 6719971; US ​​6800738; US 7074404; Coussens et al. (1985) Science 230:1132-9; Slamon et al. (1989)). Science 244:707-12; Slamon et al. (2001) New Engl. J.Med. 344:783-792). Trastuzumab has been shown to inhibit the proliferation of human tumor cells overexpressing HER2 in both in vitro assays and in animals (Hudziak et al. (1989) Mol Cell Biol 9:1165-72; Lewis et al. (1993) Cancer Immunol Immunother; 37:255-63; Baselga et al. (1998) Cancer Res. 58:2825-2831). Trastuzumab is a mediator of antibody-dependent cytotoxic ADCC (Lewis et al. (1993) Cancer Immunol Immunother 37 (4): 255-263; Hotaling et al. (1996) [Abstract]. Proc. Annual Meeting Am Assoc Cancer Res; 37:471; Pegram MD et al. (1997) [Abstract]. Proc Am Assoc Cancer Res; 38:602; Sliwkowski et al. (1999) Seminars in Oncology 26(4), Suppl 12:60-70; Yarden Y. and Sliwkowski, M. (2001) Nature Reviews: Molecular Cell Biology, Macmillan Magazines, Ltd., Vol. 2:127-137).

[0068] Herceptin® (trastuzumab) was approved in 1998 for the treatment of patients with HER2-overexpressing metastatic breast cancer who had received extensive existing anticancer therapy (Baselga et al., (1996) J. Clin. Oncol. 14:737-744), and has since been used in more than 300,000 patients (Slamon DJ et al. N Engl J Med 2001;344:783-92; Vogel CL et al. J Clin Oncol 2002;20:719-26; Marty M et al. J Clin Oncol 2005;23:4265-74; Romond EH et al. TN Engl J Med 2005;353:1673-84; Piccart-Gebhart MJ et al. N Engl J Med 2005;353:1659-72; Slamon D et al. [Abstract]. Breast Cancer Res Treat 2006, 100 (Supplement 1): 52). In 2006, the FDA approved Herceptin® (trastuzumab, Genentech) as part of a treatment regimen that includes doxorubicin, cyclophosphamide, and paclitaxel for adjuvant treatment of HER2-positive, lymph node-positive breast cancer patients.

[0069] HERCEPTIN HYLECTA™ (trastuzumab and hyaluronidase-oysk) is a combination of trastuzumab and recombinant human hyaluronidase (an endoglucosidase, a tissue permeability modifier administered via subcutaneous fluid), and has been approved by the U.S. FDA for the treatment of breast cancer that overexpresses HER2.

[0070] Pertuzumab: Pertuzumab (also known as recombinant humanized monoclonal antibody 2C4, rhuMAb 2C4, Perjeta) ®Genentech, South San Francisco (GST), represents the first in a new class of agents called HER dimerization inhibitors (HDIs) and is used to inhibit the ability of HER2 to form active heterodimers or homodimers with other HER receptors such as EGFR / HER1, HER2, HER3, and HER4. See, for example, Harari and Yarden Oncogene 19:6102-14 (2000); Yarden and Sliwkowski. Nat Rev Mol Cell Biol 2:127-37 (2001); Sliwkowski Nat StructBiol 10:158-9 (2003); Cho et al. Nature 421:756-60 (2003); and Malik et al. Pro AmSoc Cancer Res 44:176-7 (2003).

[0071] Perjeta® (pertuzumab) was first approved in 2012 for the treatment of patients with advanced or late-stage (metastatic) HER2-positive breast cancer. On September 30, 2013, the U.S. Food and Drug Administration (FDA) granted Perjeta® (pertuzumab) accelerated approval designation as part of a complete treatment regimen (neoadjuvant setting) for patients with preoperative early breast cancer (EBC). Perjeta® was the first drug approved by the FDA for neoadjuvant therapy in breast cancer.

[0072] Pertuzumab inhibits ligand-initiated intracellular signaling via major signaling pathways, including PI3K, which may lead to cell growth arrest and apoptosis. Furthermore, both trastuzumab and pertuzumab mediate antibody-dependent cytotoxicity (ADCC). Overall, the combination of pertuzumab and trastuzumab was well tolerated, with no significant increase in left ventricular systolic dysfunction.

[0073] PH FDC SC (Hergelcon): Hergacon® (pertuzumab, trastuzumab, and hyaluronidase-zzxf) contains a fixed-dose combination of pertuzumab and trastuzumab with hyaluronidase for subcutaneous injection and was approved by the U.S. FDA in 2020 for the treatment of early and metastatic HER2-positive breast cancer. Hergacon can be administered subcutaneously (SC) in combination with intravenous (IV) chemotherapy.

[0074] Herceptin is a ready-to-use formulation of Perjeta and Herceptin (PH), co-formulated in a single vial with recombinant human PH20 hyaluronidase (rHuPH20) for use in SC injections. Herceptin administration has been shown to be equivalent to IV PH in terms of PK, efficacy, and safety (Tan et al. 2021). Compared to IV administration of PH, Herceptin can be administered within 5 to 8 minutes rather than over several hours and is the preferred choice for most participants (O'Shaughnessy et al. 2020). Herceptin is a SoC and has been approved by health authorities in the same context as IV formulations: specifically, Herceptin is approved in the United States and can be administered at home by healthcare professionals. Herceptin is also approved in the European Union and many other countries worldwide. Indications include use in participants with HER2-positive EBC and ABC.

[0075] Phesgo's prescribing information is available at: www.gene.com / download / pdf / phesgo_prescribing.pdf, which is incorporated herein by reference in its entirety.

[0076] Indications and Usage Hergacon is a combination of pertuzumab and trastuzumab, a HER2 / neu receptor antagonist, and hyaluronidase (an endoglucosidase), indicated for: (1.1) Used in combination with chemotherapy as: (a) neoadjuvant therapy for patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer (diameter greater than 2 cm or nodule-positive) as part of a complete treatment regimen for early-stage breast cancer; (b) adjuvant therapy for patients with HER2-positive early-stage breast cancer at high risk of recurrence.

[0077] (1.2) Used in combination with docetaxel for the treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

[0078] Patient selection (2.1) Patients should be selected based on HER2 protein overexpression or HER2 gene amplification in tumor specimens [see Indications and Uses (1) and Clinical Studies (14)]. Evaluation of HER2 protein overexpression and HER2 gene amplification should be performed by a skilled laboratory using an FDA-approved breast cancer-specific assay. Information on FDA-approved assays for detecting HER2 protein overexpression and HER2 gene amplification is available at: www.fda.gov / CompanionDiagnostics. Incorrect assay performance, including the use of suboptimal fixed tissue, failure to use specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.

[0079] Recommended dosage and schedule (2.3) The recommended dosage and administration schedule for Herceptin are as follows: Initial dose: 1,200 mg pertuzumab, 600 mg trastuzumab and 30,000 units of hyaluronidase / 15 mL (1,200 mg, 600 mg and 30,000 units / 15 mL); administered subcutaneously over approximately 8 minutes.

[0080] Maintenance dose (administered every 3 weeks): 600 mg pertuzumab, 600 mg trastuzumab and 20,000 units of hyaluronidase / 10 mL (600 mg, 600 mg and 20,000 units / 10 mL); administered subcutaneously over approximately 5 minutes every 3 weeks.

[0081] No adjustment of Herceptin dosage is required based on patient weight or accompanying chemotherapy regimen.

[0082] Patients currently receiving intravenous pertuzumab and trastuzumab can transition to Hergacon. In patients receiving intravenous pertuzumab and trastuzumab, Hergacon is administered at a maintenance dose of 600 mg pertuzumab / 600 mg trastuzumab every 3 weeks for subsequent administration, starting <6 weeks after the previous dose. In patients receiving intravenous pertuzumab and trastuzumab, Hergacon is administered at an initial dose of 1,200 mg pertuzumab / 600 mg trastuzumab, followed by a maintenance dose of 600 mg pertuzumab / 600 mg trastuzumab every 3 weeks for subsequent administration, starting ≥6 weeks after the previous dose.

[0083] Neoadjuvant therapy for breast cancer: As part of the treatment regimen for early breast cancer, administer Hergacon every 3 weeks for 3 to 6 cycles [see Clinical Study (14.2)]. For recommended dosage and dosage adjustments, please refer to the prescribing information for pertuzumab in combination with trastuzumab and chemotherapy. Postoperatively, as part of the complete regimen for early breast cancer, patients should continue Hergacon to complete 1 year of treatment (up to 18 cycles) or until disease recurrence or uncontrollable toxicity, whichever occurs first.

[0084] Adjuvant therapy for breast cancer: As part of a complete regimen for early breast cancer (including standard anthracycline-based and / or taxane-based chemotherapy), administer Hergacon every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or uncontrollable toxicity, whichever occurs first. Start Hergacon on day 1 of the first taxane-based cycle [see Clinical Study (14.2)].

[0085] Metastatic breast cancer (MBC): When using Herceptin, the recommended initial dose of docetaxel is 75 mg / m² administered intravenously. If the initial dose is well tolerated, the dose may be increased to 100 mg / m² every 3 weeks. Herceptin should be administered until disease progression or uncontrollable toxicity occurs, whichever comes first.

[0086] Hertek describes Hergecon is a combination of pertuzumab, trastuzumab, and hyaluronidase.

[0087] Pertuzumab is a recombinant humanized monoclonal antibody that targets the extracellular dimerization domain (subdomain II) of the human epidermal growth factor receptor 2 (HER2) protein. Pertuzumab is produced in mammalian cell (Chinese hamster ovary) cultures using recombinant DNA technology. Pertuzumab has a molecular weight of approximately 148 kDa.

[0088] Trastuzumab is a humanized IgG1κ monoclonal antibody that selectively binds to the extracellular domain of the human epidermal growth factor receptor 2 (HER2) protein with high affinity. Trastuzumab is produced in mammalian cell (Chinese hamster ovary) cultures using recombinant DNA technology. Trastuzumab has a molecular weight of approximately 148 kDa.

[0089] Hyaluronidase (recombinant human) is a glycosaminoglycan used to enhance the dispersion and absorption of co-administered drugs when administered subcutaneously. It is a glycosylated single-chain protein produced by mammalian (Chinese hamster ovary) cells, containing a DNA plasmid encoding a soluble fragment of human hyaluronidase (PH20). Hyaluronidase (recombinant human) has a molecular weight of approximately 61 kDa.

[0090] Hergacon (pertuzumab, trastuzumab, and hyaluronidase-zzxf) injection is a sterile, preservative-free, clear to milky white and colorless to slightly brownish solution for subcutaneous administration, supplied in single-dose vials, supplied in cartons containing one single-dose vial. (a) 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units of hyaluronidase / 15 mL (80 mg, 40 mg, and 2,000 units / mL). In this formulation, Hergiline is supplied in a 15 mL single-dose vial containing 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units of hyaluronidase, as well as α,α-trehalose (397 mg), L-histidine (6.75 mg), L-histidine hydrochloride monohydrate (53.7 mg), L-methionine (22.4 mg), polysorbate 20 (6 mg), and sucrose (685 mg) at pH 5.5.

[0091] (b) 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units of hyaluronidase / 10 mL (60 mg, 60 mg, 2,000 units / mL). In this formulation, Hergicon is supplied in 10 mL single-dose vials containing 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units of hyaluronidase, as well as α,α-trehalose (397 mg), L-histidine (4.4 mg), L-histidine hydrochloride monohydrate (36.1 mg), L-methionine (14.9 mg), polysorbate 20 (4 mg), and sucrose (342 mg), at pH 5.5.

[0092] Further details of Hergecon are described in US 2021 / 0403599 A1, which is incorporated herein by reference.

[0093] Fulvestrant: Fulvestrant is an ER antagonist and a relatively well-tolerated and effective treatment for postmenopausal HR+ breast cancer patients. The expected toxicities of inalipate and fulvestrant do not overlap. Testing combinations of inalipate with letrozole and fulvestrant is crucial because these endocrine therapies have different mechanisms of action, different pharmacokinetic (PK) characteristics, and different potential for drug interactions (DDI) with inalipate.

[0094] Fulvestrant (FASLODEX®, AstraZeneca, CAS Registry No. 129453-61-8) has been 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 Hematol. March; 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).

[0095] 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: .

[0096] 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 after anti-estrogenic therapy. In multicenter phase III studies, fulvestrant was found to be at least equivalent to anastrozole (a nonsteroidal AI) 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 was also as effective as tamoxifen (Howell et al. (2004) J Clin Oncol 22:1605-1613), and showed similar activity to the nonsteroidal AI exemestane in patients with metastatic disease following AI (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 Oncol 27:4530-4535). High-dose fulvestrant has recently demonstrated 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 United States and the European Union (2010) for postmenopausal women whose disease has spread after treatment with AI.These studies demonstrate that fulvestrant is an important treatment option for patients with advanced breast cancer and is therefore considered an appropriate control therapy for this study.

[0097] Letrozole: Letrozole is a relatively well-tolerated and effective treatment for postmenopausal HR+ breast cancer patients. The expected toxicities of enoxaparin and letrozole do not overlap. Letrozole (FEMARA®, Novartis) is an oral nonsteroidal aromatase inhibitor used to treat postoperative hormone-responsive breast cancer (Bhatnagar et al. (1990) J. Steroid Biochem. and Mol. Biol. 37:1021; Lipton et al. (1995) Cancer 75:2132; Goss, PE and Smith, RE (2002) Expert Rev. Anticancer Ther. 2:249-260; Lang et al. (1993) The Journal of Steroid Biochem. and Mol. Biol. 44 (4–6):421–8; EP 236940; US4978672). FEMARA® has been approved by the FDA for the treatment of postmenopausal women with hormone receptor-positive (HR+) or unknown receptor status locally or metastatic breast cancer.

[0098] Letrozole is named 4,4'-((1H-1,2,4-triazol-1-yl)methylene)dibenzylnitrile (CAS Registry No. 112809-51-5) and has the following structure: .

[0099] Paclitaxel: Paclitaxel is a chemotherapy drug approved for use as a monotherapy or in combination with other anticancer agents to treat various types of cancer (e.g., ovarian cancer, breast cancer, lung cancer, etc.). Paclitaxel is named as the 13-ester of 5β,20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytaxane-11-en-9-one 4,10-diacetate 2-benzoate and (2R,3S)-N-benzoyl-3-phenylisoserine, and has the following structure: .

[0100] Combination therapy In human epidermal growth factor receptor 2-positive (HER2+) breast cancer, dysregulation of the PI3K / AKT / mTOR pathway (in the form of activating mutations and other aberrations) has been identified as a possible mechanism of resistance to HER2-targeted therapy. Thus, sustained inhibition of the HER2 pathway and co-targeting of the PI3K / AKT / mTOR pathway may restore sensitivity to HER2-targeted therapy. Adding a PI3K inhibitor to trastuzumab and pertuzumab can improve the prognosis of patients with PIK3CA-mutant HER2+ breast cancer.

[0101] This article provides combination or combination therapy comprising inalipase and a fixed-dose combination (PH FDC SC or Hergacon) of pertuzumab and trastuzumab for subcutaneous injection. In some embodiments, the combination therapy comprises 9 mg of inalipase administered orally daily (PO, QD) and 600 mg of pertuzumab, 600 mg of trastuzumab, and recombinant human PH20 hyaluronidase (rHuPH20) administered subcutaneously every three weeks (SC, Q3W).

[0102] 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 Hergamox. In one embodiment, the kit comprises enoxacillin, pertuzumab, trastuzumab, and hyaluronidase-zzxf. In one embodiment, the kit comprises enoxacillin, pertuzumab, trastuzumab, and rHuPH20. In one embodiment, the kit comprises 9 mg of enoxacillin oral tablets and a maintenance dose of PH FDC SC (Hergamox), which comprises 600 mg of pertuzumab, 600 mg of trastuzumab, and rHuPH20 SC for subcutaneous injection. In one embodiment, the kit may further comprise a loading dose of PH FDC SC (Hergamox), which comprises 1200 mg of pertuzumab, 600 mg of trastuzumab, and rHuPH20 SC for injection. In one embodiment, the agents of the combination or combination therapies described herein are provided in the form of an easily administerable kit. The kit described herein may include instructions for use, such as packaging inserts. In one embodiment, the instructions for use are packaging inserts, with one packaging insert provided for each drug in the kit.

[0103] Furthermore, a kit is provided for carrying out the methods detailed herein, which comprises the pharmaceutical composition or combination therapy described herein and instructions for use in the treatment of breast cancer.

[0104] 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.

[0105] method HER2 overexpression is an important prognostic and predictive biomarker for metastatic breast cancer (Pauletti et al. 2000). In a phase III study of trastuzumab plus docetaxel with or without pertuzumab in patients with 1L HER2+ mBC, above-median (high) HER2 protein expression as determined by immunohistochemistry and above-median (high) HER2 mRNA expression as determined by qRT-PCR (quantitative reverse transcription polymerase chain reaction) were significantly associated with better prognosis in this patient population (HR 0.83 [p = 0.05] and HR 0.77 [p = 0.008], respectively) (Baselga et al. 2014). Frequent PIK3CA mutations have also been observed in patients with HER2 expression, and the incidence of PIK3CA mutations varies. According to IHC, the incidence of PIK3CA mutations in patients with focal, heterogeneous HER2 expression was observed to be almost twice that in patients with stable, homogeneous HER2 expression (24%) (Perez et al. 2019). Therefore, the combination of mutant PI3Kα inhibitors and HER2-targeted therapy is beneficial for the treatment of HER2+ breast cancer.

[0106] Not all PI3Kα inhibitors are created equal. Enallix is ​​particularly effective than another clinically relevant PI3Kα inhibitor, alpelisib (also known as BYL719), in inhibiting the growth of HER2+ PIK3CA mutant cancer cells. In a study comparing the efficacy of enallix and alpelisib, significant differences were found in the sensitivity of enallix and alpelisib in HER2-amplified cell lines (with an approximately 20-fold difference in mean IC50 values) versus HER2-negative cell lines (with a 6-fold difference between the two inhibitors). There was no difference between the two inhibitors in PIK3CA-WT cell lines regardless of HER2 status.

[0107] This article provides a method for treating HER2-positive cancer. In one embodiment, the method includes treating a patient with locally advanced or metastatic PIK3CA-mutated HER2-positive breast cancer by administering a combination therapy comprising enoxaparin and a HER2-targeted therapy such as PH FDC SC (Hergacon). The combination therapy is administered as maintenance therapy after the patient has received induction therapy, which comprises a taxane-based chemotherapy (e.g., paclitaxel, docetaxel, or albumin-bound paclitaxel) and pertuzumab and trastuzumab (PH) or PH FDC SC (Hergacon). The choice between PH and IV SC formulations enhances the flexibility of care and improves the patient experience.

[0108] It also provides a method for treating patients with locally advanced or metastatic PIK3CA-mutated (or PIK3CA mutant) HER2-positive breast cancer, the method comprising administering a therapeutically effective amount of inalipse or a pharmaceutically acceptable salt thereof and PH FDC SC (Hergacon).

[0109] In some embodiments, a method is provided for treating HER2-positive breast cancer in a patient with locally advanced or metastatic PIK3CA-mutated HER2-positive breast cancer, the method comprising administering a combination therapy to the patient comprising: enoxaparin and PH FDC SC (Hergacon); wherein the combination therapy is administered over a 21-day cycle.

[0110] In some embodiments, a method is provided for treating HER2-positive breast cancer in a patient with locally advanced or metastatic PIK3CA-mutated HER2-positive breast cancer, the method comprising administering a combination therapy to the patient comprising a dosing regimen including: a. Administer inolic acid on days 1 through 21 of the first 21-day cycle (QD); and b. Administer PH FDC SC (Herbacare) on day 1 of the first 21-day cycle.

[0111] In some embodiments of these examples, the method further includes one or more additional 21-day cycles, which include: a. Administer inarise on days 1 through 21 of each additional 21-day cycle; and b. Administer PH FDC SC (Hergacon) on day 1 of each additional 21-day cycle.

[0112] In some embodiments, prior to administration of the combination therapy comprising enoxacillin and PH FDC SC, the patient receives induction therapy, which includes administration of pertuzumab and trastuzumab (perjeta and Herceptin, or PH) and taxane-based chemotherapy. In some embodiments, the induction therapy includes administration of PH FDC SC and taxane-based chemotherapy (e.g., paclitaxel, docetaxel, or nano-albumin-bound paclitaxel). In some embodiments, the induction therapy includes a dosing regimen comprising four (4) to eight (8) (e.g., 4, 5, 6, or 8) 21-day cycles: (a) administration of PH FDC SC on day 1 of each 21-day cycle; and (b) administration of paclitaxel on days 1, 8, and 15 of each 21-day cycle. In some embodiments, the induction therapy includes a dosing regimen comprising four (4) to eight (8) 21-day cycles of: (a) administration of PH FDC SC on day 1 of each 21-day cycle; and (b) administration of taxane-based chemotherapy according to SoC (e.g., administration of docetaxel or nano-albumin-bound paclitaxel on day 1 of each 21-day cycle).

[0113] In some embodiments, patients are treated with maintenance therapy following induction therapy, which includes inoralise and PH FDC SC (Hergecare).

[0114] In some embodiments, a method of treating HER2-positive breast cancer in a patient with locally advanced or metastatic PIK3CA-mutated HER2-positive breast cancer is provided, the method comprising administering induction therapy followed by maintenance therapy to the patient. In some embodiments, the induction therapy comprises a dosing regimen comprising 4 to 8 21-day cycles: administration of PH FDC SC (Hergacon) on day 1 of each 21-day cycle; and administration of a taxane-based chemotherapy (e.g., paclitaxel on days 1, 8, and 15 of each 21-day cycle, or docetaxel or nano-albumin-bound paclitaxel on day 1 of each 21-day cycle). In some embodiments, the maintenance therapy comprises a dosing regimen comprising one or more 21-day cycles: administration of enoxaparin on days 1 to 21 of each 21-day cycle; and administration of PH FDC SC (Hergacon) on day 1 of each 21-day cycle.

[0115] In some embodiments, the induction therapy includes a dosing regimen comprising four to eight 21-day cycles: administration of PH FDC SC (Hergacon) containing 600 mg pertuzumab, 600 mg trastuzumab, and rHuPH20 SC on day 1 of each 21-day cycle; and administration of taxane-based chemotherapy according to its prescribing information, such as weekly administration of paclitaxel on days 1, 8, and 15 of each 21-day cycle, or administration of docetaxel or nano-albumin-bound paclitaxel on day 1 of each 21-day cycle. In some embodiments, the induction therapy may further include administration of a loading dose of PH FDC SC (Hergacon) containing 1200 mg pertuzumab, 600 mg trastuzumab, and rHuPH20 SC on day 1 of the first 21-day cycle.

[0116] In some embodiments, maintenance therapy includes a dosing regimen comprising one or more 21-day cycles: administration of 9 mg inalipsa (e.g., in oral tablets) on days 1 through 21 of each 21-day cycle; and administration of PH FDC SC (Hergacon) containing 600 mg pertuzumab, 600 mg trastuzumab, and rHuPH20 SC on day 1 of each 21-day cycle. In some embodiments, if a patient misses any cycle of Hergacon and the time between doses is ≥ 6 weeks, a loading dose of PH FDC SC (Hergacon) (1200 mg pertuzumab, 600 mg trastuzumab, and rHuPH20 SC) is administered.

[0117] Based on dose-limiting toxicities (DLTs) observed in patients, enoxacillin can be administered on a 6 / 1 or 5 / 2 dosing schedule. Enallicil is administered 6 days a week with 1 day of rest, or 5 days a week with 2 days of rest.

[0118] In some embodiments, a method of treating HER2-positive breast cancer in a patient with locally advanced or metastatic PIK3CA-mutated HER2-positive breast cancer is provided, the method comprising administering to the patient a maintenance therapy comprising a dosing regimen including: a. Administer inarise on days 2 to 7, 9 to 14, and 16 to 21 of each 21-day cycle; and b. Apply PH FDC SC (Hergacon) on day 1 of each 21-day cycle.

[0119] In some embodiments, a method of treating HER2-positive breast cancer in a patient with locally advanced or metastatic PIK3CA-mutated HER2-positive breast cancer is provided, the method comprising administering to the patient a maintenance therapy comprising a dosing regimen including: a. Administer inarise on days 3 to 7, 10 to 14, and 17 to 21 of each 21-day cycle; and b. Apply PH FDC SC (Hergacon) on day 1 of each 21-day cycle.

[0120] Following 4 to 8 cycles of induction therapy consisting of PH FDC SC (Hergacon) and a taxane-based chemotherapy (e.g., paclitaxel, docetaxel, or nano-albumin-bound paclitaxel), patients may continue with one or more cycles of maintenance therapy consisting of enoxaparin and PH FDC SC (Hergacon) until disease progression or unacceptable associated toxicities occur. During maintenance therapy, patients with HR-positive / HER2-positive metastatic breast cancer may be treated with endocrine therapy (e.g., fulvestrant or aromatase inhibitors such as letrozole).

[0121] In one embodiment, the method includes a combination therapy comprising enoxacillin and PH FDC SC (Hergacon). In one embodiment, the method includes maintenance therapy comprising enoxacillin and PH FDC SC (Hergacon) according to the dosing regimen described herein. In one embodiment, the method includes induction therapy comprising administration of PH FDC SC (Hergacon) and a taxane-based chemotherapy (e.g., paclitaxel, docetaxel, or nano-albumin-bound paclitaxel) according to the dosing regimen described herein.

[0122] In another aspect, a method is provided for inhibiting tumor growth or producing / increasing tumor regression in a patient with locally advanced or metastatic PIK3CA-mutated HER2-positive breast cancer, the method comprising administering combination therapy to the patient according to the methods detailed herein.

[0123] The medications described herein can be administered according to the package insert. In one embodiment of the methods described herein, the medication may be administered in an effective amount as described herein. The medications in the combination therapies detailed herein may be administered simultaneously or sequentially. In one embodiment, enoxaparin is administered before or after PH FDC SC (Hergelcan).

[0124] In some embodiments, enoxacillin is administered in doses of 3, 6, or 9 mg, for example, in the form of 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, for example, in the form of oral tablets. In some embodiments, enoxacillin is administered orally at a daily dose of 6 mg, for example, in the form of one or more oral tablets.

[0125] In some embodiments of induction therapy, paclitaxel is administered via intravenous (IV) infusion. In some embodiments, paclitaxel is administered at a dose of 80 mg / m² per week. 2 Administered at the prescribed dose. In some embodiments, paclitaxel is administered at a dose of 80 mg / m² per week. 2 The dosage is administered via intravenous infusion.

[0126] In one embodiment, the method described herein includes administering the combination therapy described herein according to a dosing regimen comprising a 21-day cycle. In another embodiment, the method described herein includes the combination therapy described herein, administered according to a dosing regimen comprising a first 21-day cycle followed by a further 21-day cycle. In another embodiment, the method described herein includes the maintenance therapy described herein, administered according to a dosing regimen comprising a first 21-day cycle followed by 2 to 30 further 21-day cycles, or until disease progression or unacceptable toxicity occurs. In another embodiment, the method described herein includes the induction therapy described herein, administered according to a dosing regimen comprising a first 21-day cycle followed by up to seven further 21-day cycles, or until disease progression or unacceptable toxicity occurs. In another embodiment, the method described herein includes the induction therapy described herein, administered according to a dosing regimen comprising a first 21-day cycle followed by three to seven further 21-day cycles; and the maintenance therapy described herein, administered according to a dosing regimen comprising one or more 21-day cycles (e.g., up to 30 further 21-day cycles), or until disease progression or unacceptable toxicity occurs.

[0127] The effectiveness of the measurement combination varies with progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and other relevant clinical outcomes.

[0128] In some embodiments, the patient has HER2-positive locally advanced or metastatic breast cancer with a PIK3CA mutation. In some embodiments, the patient is a female patient with histologically documented locally advanced or metastatic HER2+ breast cancer with a PIK3CA mutation. The patient's hormone receptor status can be positive or negative. In some embodiments, the patient has hormone receptor-positive (HR+), locally advanced or metastatic HER2-positive breast cancer with a PIK3CA mutation. In some embodiments, the patient has hormone receptor-negative (HR–), locally advanced or metastatic HER2-positive breast cancer with a PIK3CA mutation.

[0129] In some embodiments, the patient has a mutant PIK3CA with mutations at one or more of the following locations: 88, 106, 111, 118, 345, 420, 453, 542, 545, 546, 1043, 1047, and 1049. In some embodiments, the patient has a mutant PIK3CA with mutations at one or more of the following locations: H1047, E545, E542, Q546, N345, C420, M1043, G1049, E453, K111, G106, G118, and R88. In some embodiments, the patient has 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 mutant 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 mutant 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 mutant selected from the group consisting of: H1047R / Y / L, E542K, E545K / D / G / A, Q546K / R / E / L, N345K, C420R, G1049R, R88Q, and M1043I. In some embodiments, the patient has breast cancer expressing a PIK3CA mutant selected from the group consisting of: E542K, E545K, Q546R, H1047L, and H1047R.

[0130] 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 mutant expressing 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.

[0131] PIK3CA mutant tumor status can be assessed through central hematology testing or in-hospital testing of blood or tumor tissue. In some embodiments, the central test for identifying eligible PIK3CA mutations is the FoundationOne fluid clinical trial assay 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.

[0132] The HER2 status of a tumor can be assessed by detecting HER2 protein overexpression and / or HER2 gene amplification in tumor specimens using known methods, such as FDA-approved assays for detecting HER2 protein overexpression and HER2 gene amplification, preferably performed by a certified laboratory using FDA-approved assays specific to breast cancer. HER2+ is defined as: (i) a HER2 IHC score of 3+; (ii) a HER2 IHC score of 2+ with a dual-probe ISH HER2 / CEP17 ratio of ≥ 2.0 (preferably); (iii) fluorescence, chromogenic, or silver ISH assays indicating the presence of HER2 gene amplification; or (iv) HER2+ according to local clinical guidelines.

[0133] In some embodiments, the patient is a female with histologically documented locally advanced or metastatic PIK3CA-mutated HER2+ breast cancer. In some embodiments, the patient has a HER2 IHC score of 3 or higher. In some embodiments, the patient has a HER2 IHC score of 2 or higher, with a dual-probe ISH HER2 / CEP17 ratio of not less than 2.0 (preferably). In some embodiments, the patient has fluorescent, chromogenic, or silver ISH assays indicating the presence of HER2 gene amplification. In some embodiments, the patient is HER2+ according to local clinical guidelines. In some embodiments, the patient has a fasting blood glucose level equal to or less than 140 mg / dL. In some embodiments, the patient has less than 7% glycosylated hemoglobin (HbA1c). 1c Level. In some embodiments, the patient has a left ventricular ejection fraction (LVEF) of ≥ 50%. LVEF can be determined by echocardiography (ECHO) (preferably) or multi-gated acquisition (MUGA) scan. In some embodiments, the patient has received prior HER2-targeted therapy (e.g., trastuzumab and / or pertuzumab) and has not discontinued prior HER2-targeted therapy (e.g., trastuzumab and / or pertuzumab) due to toxicity assessed as related to the prior HER2-targeted therapy (e.g., trastuzumab and / or pertuzumab).

[0134] Patients may have HR+ or HR- breast cancer. HR+ is defined as ER expression in ≥ 1% of cells, or HR+ according to local clinical guidelines. HR- is defined as ER expression in <1% of cells, or HR- according to local clinical guidelines. Patients with HR+ breast cancer may be treated with endocrine therapy (e.g., letrozole or fulvestrant), and premenopausal or perimenopausal patients may also be treated with LHRH agonist therapy, at the investigator's discretion.

[0135] In some embodiments, the patient has HR+, locally advanced or metastatic PIK3CA mutant HER2+ breast cancer, and the treatment includes administering a combination therapy to the patient comprising: enoxaparin and PH FDC SC (Hergacon), and endocrine therapy (e.g., fulvestrant or aromatase inhibitors such as letrozole).

[0136] In some embodiments, a method is provided for treating a patient with HR+, locally advanced, or metastatic PIK3CA-mutated HER2+ breast cancer, the method comprising administering to the patient a therapeutically effective amount of inaliprine or a pharmaceutically acceptable salt thereof, PH FDC SC (Hergacon), and endocrine therapy (e.g., letrozole or fulvestrant). In some embodiments, the endocrine therapy is letrozole administered according to its approved label (e.g., administered daily as an oral tablet at a dose of 2.5 mg). In some embodiments, the endocrine therapy is fulvestrant administered according to its approved label (e.g., administered approximately every four weeks via intramuscular (IM) infusion at a dose of 500 mg).

[0137] In one embodiment of the methods described herein, the patient has 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, the prior therapy includes HER2-targeted therapy (e.g., trastuzumab, pertuzumab, or a combination of trastuzumab and pertuzumab). In another embodiment, the patient described herein has not previously been treated with HER2-targeted therapy (e.g., trastuzumab, pertuzumab, or a combination of trastuzumab and pertuzumab).

[0138] 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 HER2-targeted therapies like trastuzumab or pertuzumab. 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 site or a 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.

[0139] Co-administration of inalipase with PH FDC SC (Hergacon) can prevent or delay the development of resistance in tumors (e.g., breast cancer) to HER2-targeted therapies (e.g., trastuzumab, pertuzumab, or a combination of trastuzumab and pertuzumab). Therefore, a method for preventing or delaying the development of resistance in tumors (e.g., breast cancer) to therapies containing HER2-targeted therapies (e.g., trastuzumab, pertuzumab, or a combination of trastuzumab and pertuzumab) is provided, 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 therapies containing trastuzumab and / or pertuzumab is provided, comprising administering a combination therapy comprising trastuzumab and / or pertuzumab, or a combination therapy comprising inalipase, trastuzumab, and pertuzumab. In some embodiments, the combination therapy is administered according to any method detailed herein.

[0140] biomarkers 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.

[0141] 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).

[0142] Circulating tumor DNA (ctDNA) can be detected in the blood of cancer patients with epithelial carcinoma and can be of diagnostic and therapeutic significance (Schwarzenbach et al., Nat Rev Cancer 2011; 11:426–437). 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 evaluate baseline oncogene alterations and to assess new alterations that may occur after treatment with enoxaparin and HER2-targeted therapy.

[0143] Example abbreviation: AE, adverse events; AUC 0–24 The 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 relief; 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; PD, pharmacodynamics; PrD, disease progression; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α; PK, pharmacokinetics; PR, partial relief; pts: patient RECIST, Clinical efficacy evaluation criteria for solid tumors; SD, the disease is stable; SLD, the sum of the longest diameters; TRAE, treatment-related adverse events.

[0144] Example 1: A phase III, multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of inoralise plus ecstasy versus placebo plus ecstasy as maintenance therapy following first-line induction therapy in participants with PIK3CA-mutated HER2-positive locally advanced or metastatic breast cancer. A phase III study is underway to evaluate the efficacy and safety of inalipase in combination with PH FDC SC (Hergacon®; pertuzumab, trastuzumab and rHuPH20 injection for subcutaneous use) versus placebo in combination with PH FDC SC as maintenance therapy following first-line induction therapy in patients with PIK3CA-mutated HER2+, unresectable LA / mBC.

[0145] The study design is shown in Figure 1. Eligible patients were enrolled either as first-line induction therapy (if they were receiving / would receive PH + taxane) followed by maintenance therapy, or as maintenance therapy (if they completed out-of-study induction therapy). During the maintenance period, patients were randomized 1:1 to receive either enoxaparin (9 mg, orally once daily from day 1 to day 21 of a 21-day cycle) + PH FDC SC (Hergacon) (every 3 weeks) or placebo + PH FDC SC (Hergacon).

[0146] Induction therapy consists of PH FDC SC (Hergaline) plus a taxane-based chemotherapy (e.g., paclitaxel, docetaxel, or nano-albumin-bound paclitaxel). During the induction therapy phase, PH FDC SC (Hergaline) is administered subcutaneously to participants every 3 weeks (Q3W) on day 1 of each 21-day cycle, followed by an investigator-selected taxane-based chemotherapy.

[0147] Maintenance therapy consisted of enoxaparin plus PH FDC SC (Hergacon). During the maintenance period, participants received oral (PO) enoxaparin tablets once daily (QD) from day 1 of treatment cycle (C) 1 through day 21 of each 21-day cycle, and subcutaneous PH FDC SC (Hergacon) every 3 weeks (Q3W) on day 1 of each 21-day cycle. Based on standard of care, investigators may choose endocrine therapy (ET) at their discretion. Permitted ETs were tamoxifen, or one of the designated third-generation aromatase inhibitors (AI [anastrozole, letrozole, or exemestane]), or fulvestrant. Investigators identified and provided an appropriate luteinizing hormone-releasing hormone (LHRH) agonist approved locally for breast cancer. LHRH agonists were administered according to local prescribing information.

[0148] In the control arm of the maintenance period, participants received a placebo plus PH FDC SC (Hergaline). Starting on maintenance therapy day 1 (C1), participants received a matched tablet of enoxaparin via PO QD on days 1 through 21 of each 21-day cycle; and PH FDC SC (Hergaline) was administered to participants every 3 weeks (Q3W) on day 1 of each 21-day cycle. Based on standard of care, the investigator may decide on optional endocrine therapy (ET). Permitted ETs include tamoxifen, or one of the specified third-generation aromatase inhibitors (AI [anastrozole, letrozole, or exemestane]), or fulvestrant. The investigator identified and provided an appropriate luteinizing hormone-releasing hormone (LHRH) agonist approved locally for breast cancer. The LHRH agonist was administered according to local prescribing information.

[0149] The primary endpoint analysis employed a two-sided stratified log-rank test with a two-sided significance level of 5%. A stratified Cox proportional hazards model was used to estimate the hazard ratio between the two treatment arms and its 95% confidence interval.

[0150] Stratification factors included (i) primary HER2+ unresectable LA / metastatic disease compared to recurrent disease, (ii) HR+ compared to HR- tumor status, and (iii) objective response after induction therapy: PR / CR compared to SD (or non-CR / non-disease progression in patients with unmeasurable disease).

[0151] The primary endpoint of the study included investigator-assessed progression-free survival (PFS), defined as the time from randomization to the first occurrence of disease progression (according to the RECIST v1.1 criteria for clinical efficacy evaluation in solid tumors) or death from any cause (whichever comes first). [Time range: up to approximately 40 months] Secondary endpoints of the study included: (i) Total OS [Time range: up to approximately 111 months] (ii) Investigator-assessed objective response rate (ORR) [time range: up to approximately 111 months], (iii) Investigator-assessed duration of remission (DOR) [time range: up to approximately 111 months], (iv) Investigator-assessed clinical benefit rate (CBR) [time range: up to approximately 111 months], (v) Investigator-assessed time to second disease progression (PFS2) [time range: up to approximately 111 months], (vi) Patient-reported outcomes / health-related quality of life (HRQoL) [Timeframe: Day 1 of Cycle 1 and Cycle 2 and thereafter, 30-day safety follow-up visit, post-treatment tumor assessment follow-up, and PRO collection and survival follow-up visits, every 6 months (maximum 111 months). Each cycle is 21 days.] (vii) Percentage of participants experiencing adverse events (safety) [Time range: Day 1 to 30 days after the last dose of study treatment (maximum approximately 111 months). Each cycle is 21 days.]; and (viii) Plasma concentrations of enoxacillin at specified time points (pharmacokinetics) [Time range: Day 1 of cycle 1 and cycle 4. Each cycle is 21 days.] Main inclusion criteria : 1. Eastern Cooperative Oncology Group (ECOG) performance status is 0 or 1; 2. HER2+, PIK3CA mutation diseases confirmed by the center; 3. According to the HR status recorded in the local assessment; 4. Radical resection is not suitable for LA / mBC confirmed by histology or cytology; 5. The disease-free interval from completion of adjuvant or neoadjuvant systemic non-hormonal therapy to relapse is ≥ 6 months; 6. Asymptomatic CNS metastases or CNS metastases controlled with antiepileptic drugs do not require local treatment or corticosteroids during randomization; 7. At least 50% LVEF (left ventricular ejection fraction) as measured by echocardiography (ECHO) or multi-gated acquisition scanning (MUGA); and 8. Fasting blood glucose <126 mg / dL and HbA1c <6.4%.

[0152] Maintenance period inclusion criteria : 1. Four to eight cycles of induction therapy have been completed; 2. Achieve PR, CR, SD, or non-CR / non-PR results according to RECIST v1.1 after induction therapy; 3. LVEF ≥ 50% (determined by ECHO or MUGA); and 4. Perform thorough hematological, organ function, and serological examinations during randomization.

[0153] Key Exclusion Criteria 1. Prior treatment in unresectable LA / mBC settings with any agent whose mechanism of action inhibits the PI3K / AKT / mTOR pathway; 2. Administer systemic non-hormonal anticancer therapy targeting HER2+ unresectable LA / mBC prior to initiating induction therapy; 3. History of inflammatory bowel disease or active inflammatory bowel disease; 4. Disease progression within 6 months of receiving HER2-targeted therapy; 5. Type 2 diabetes requiring continuous systemic treatment at the time of enrollment in the study, or any history of type 1 diabetes; 6. Clinically significant active liver disease, including severe liver dysfunction, viral hepatitis or other hepatitis, current alcoholism, or cirrhosis; 7. Symptomatic active lung disease, including pneumonia or interstitial lung disease; 8. History of leptomeningeal disease or carcinomatous meningitis; 9. Severe infections requiring intravenous antibiotics within 7 days prior to day 1 of cycle 1; and 10. Active inflammatory or infectious eye disease, or an eye disease that requires medical or surgical intervention during research treatment.

[0154] 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 set forth 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 purposes of limitation.

Claims

1. A method of treating HER2-positive breast cancer in a patient having locally advanced or metastatic PIK3CA-mutated HER2-positive breast cancer, the method comprising administering to the patient a combination therapy comprising infigratinib and PHE FDC SC, wherein the combination therapy is administered over 21 -day cycles.

2. A method of treating HER2-positive breast cancer in a patient having locally advanced or metastatic PIK3CA-mutated HER2-positive breast cancer, the method comprising administering to the patient a combination therapy comprising a dosing regimen comprising: a. infigratinib administered QD on Days 1-21 of a first 21 -day cycle; and b. PHE FDC SC administered on Day 1 of the first 21 -day cycle.

3. The method of claim 1 or 2, wherein prior to administering the combination therapy comprising infigratinib and PHE FDC SC, the patient has received induction therapy comprising administration of pertuzumab, trastuzumab, and a taxane-based chemotherapy.

4. The method of claim 3, wherein the induction therapy comprises administration of PHE FDC SC and a taxane-based chemotherapy.

5. The method of claim 4, wherein the taxane-based chemotherapy is paclitaxel.

6. The method of claim 5, wherein the induction therapy comprises a dosing regimen comprising four (4) to eight (8) 21 -day cycles of a. PHE FDC SC administered on Day 1 of each 21 -day cycle; and b. paclitaxel administered on Days 1, 8, and 15 of each 21 -day cycle.

7. The method of any one of claims 1-6, further comprising one or more additional 21 -day cycles comprising: a. infigratinib administered on Days 1-21 of each additional 21 -day cycle; and b. PHE FDC SC administered on Day 1 of each additional 21 -day cycle.

8. The method of any one of claims 1-7, wherein infigratinib is administered in an amount of 9 mg.

9. The method of claim 8, wherein infigratinib is administered in an amount of 9 mg as an oral tablet.

10. The method of any one of claims 1-9, wherein the PHE FDC SC administered comprises 600 mg pertuzumab, 600 mg trastuzumab, and rHuPH20 SC.

11. The method of any one of claims 1-10, wherein the patient has a left ventricular ejection fraction (LVEF) of 50% or greater. ​ 12. The method of any one of claims 1 to 11, wherein the patient has hormone receptor positive (HR+) locally advanced or metastatic PIK3CA-mutated, HER2-positive breast cancer.

13. The method of claim 12, wherein the method further comprises administering fulvestrant to the patient at a dose of 500 mg once about every four weeks by intramuscular (IM) infusion.

14. The method of claim 12, wherein the method further comprises administering an aromatase inhibitor to the patient.

15. The method of claim 14, wherein the aromatase inhibitor is anastrozole, letrozole, or exemestane.

16. A method of inhibiting tumor growth or producing / increasing tumor regression in a patient having locally advanced or metastatic PIK3CA-mutated, HER2-positive breast cancer, the method comprising administering a combination therapy to the patient according to the method of any one of claims 1 to 15.

17. A method of preventing or delaying resistance of a breast cancer to HER2-targeted therapy, the method comprising administering a combination therapy comprising infigratinib and HP FDC SC according to the method of any one of claims 1 to 16.

18. A combination therapy comprising infigratinib and HP FDC SC for use in the treatment of PIK3CA-mutated, HER2-positive breast cancer.

19. Use of a combination therapy comprising infigratinib and HP FDC SC in the manufacture of a medicament for the treatment of PIK3CA-mutated, HER2-positive breast cancer.

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