Combination therapies for treatment of her2 cancer

Abstract

Provided are combination therapies comprising inavolisib and a fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC) for the treatment of HER2-positive cancers; and methods of treating a PIK3CA mutated, HER2 positive (HER2+) locally advanced or metastatic breast cancer comprising administering a therapeutically effective amount of inavolisib and PH FDC SC.

Description

COMBINATION THERAPIES FOR TREATMENT OF HER.2 CANCERCROSS-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 content of which is incorporated by reference herein in its entirety.FIELD OF THE INVENTION[00021 The invention relates generally to treatment of PIK3CA-mutated HER2 -positive locally advanced or metastatic breast cancer, in patients by administering inavolisib in combination with a fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC).BACKGROUND

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

[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 generate phosphatidylinositol-3,4,5-triphosphate (PIP3), a second messenger involved in the phosphorylation of AKT and other components in the AKT / mTOR pathway. Up to 70% of breast cancers have some form of molecular aberration of the PI3K / AKT / mTOR pathway. Activating mutations in PIK3CA, encoding the pl 10a subunit of PI3K, are highly prevalent in breast cancer and solid tumor malignancies.

[0005] While inhibitors of PI3Ka have been approved or in clinical development for the treatment of patients with hormone receptor (HR)-positive, HER2-negative, locally advanced or metastatic breast cancer with a PIK3CA mutation, there remains a need for active agents for treatment of HER2-positive cancers.SUMMARY OF THE INVENTION

[0006] The present disclosure provides a combination therapy comprising inavolisib in combination with a fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC or Phesgo®) for the treatment of HER2-overexpressing breast cancer.1#4077844

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

[0008] The disclosure further provides methods of treating locally advanced or metastatic PIK3CA-mutated (or PIK3CA mutant) HER2-positive breast cancer comprising administering to a patient in need thereof a therapeutically effective amount of inavolisib and PH FDC SC.

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

[0010] In one aspect, provided is 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 inavolisib and PH FDC SC. In some embodoments, the combination therapy is administered over a 21-day cycle.

[0011] In one aspect, provided is 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. administering inavolisib QD on days 1-21 of a first 21-day cycle; and b. administering PH FDC SC on day 1 of a first 21-day cycle.

[0012] The method may further comprise one or more additional 21-day cycles comprising: a. administering inavolisib on days 1-21 of each additional 21-day cycle; and b. administering PH FDC SC on day 1 of each additional 21-day cycle.

[0013] In some embodiments, the patient has received an induction therapy comprising administering pertuzumab and trastuzumab (Peijeta and Herceptin, or PH) and a taxane-based chemotherapy prior to administering the combination therapy comprising inavolisib and PH FDC SC. In some embodiments, the induction therapy comprises administering PH FDC SC and a taxane-based chemotherapy (e.g., paclitaxel). Other examples of taxane-based chemotherapies include docetaxel and nab-paclitaxel. In some embodiments, the induction therapy comprises a dosing regimen comprising four (4) to eight (8) 21-day cycles of (a) administering PH FDC SC on day 1 of each 21-day cycle; and (b) administering paclitaxel on days 1, 8 and 15 of each 21-day cycle. In some embodiments, the induction therapy comprises a dosing regimen comprising four (4) to eight (8) 21-day cycles of (a) administering PH FDC SC on day 1 of each 21-day cycle; and (b) administering a taxane-based chemotherapy per SoC (e.g., administering docetaxel or nab- paclitaxel on day 1 of each 21-day cycle).

[0014] In some of these embodimnets, inavolisib is administered at an amount of 9 mg, e.g., in 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 comprises administering to the patient an endocrine therapy (e.g., fulvestrant or an aromatase inhibitor).

[0016] In some embodiments, the method further comprises administering to the patient fulvestrant, e.g., once about every four weeks at a dose of 500 mg by intramuscular (IM) infusion.

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

[0018] Also provided is a combination for use in treating locally advanced or metastatic PIK3CA-mutated (or PIK3CA mutant) HER2-positive breast cancer wherein said combination comprises inavolisib, or a pharmaceutically acceptable salt thereof, and PH FDC SC (Phesgo).

[0019] Also provided is a use of a combination in the manufacture of a medicament for treating locally advanced or metastatic PIK3CA-mutated (or PIK3CA mutant) HER2-positive breast cancer wherein said combination comprises inavolisib, or a pharmaceutically acceptable salt thereof, and PH FDC SC (Phesgo).

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

[0021] In another aspect, provided is a combination for use in inhibiting tumor growth or producing / increasing tumor regression in a patient having locally advanced or metastatic PIK3CA-mutated HER2-positive breast cancer, according to the combination for use detailed herein.

[0022] In another aspect, provided is a use of a combination in the manufacture of a medicament for inhibiting tumor growth or producing / increasing tumor regression in a patient having locally advanced or metastatic PIK3CA-mutated HER2-positive breast cancer, according to the combinations or uses detailed herein.

[0023] Further provided is a method of preventing or delaying development of resistance of a tumor (e.g., breast cancer) to a therapy containing a HER2 -targeted therapy, said method comprising administering a combination therapy comprising inavolisib and PH FDC SC (Phesgo).In some embodiments, the combination therapy is administered according to any methods as detailed herein.

[0024] Also provided is a combination for use in preventing or delaying development of resistance of a tumor (e.g., breast cancer) to a therapy containing a HER2 -targeted therapy, wherein said combination comprises inavolisib and PH FDC SC (Phesgo). In some embodiments, said combination is administered according to any uses as detailed herein.

[0025] Also provided is a use of a combination in the manufacture of a medicament for preventing or delaying development of resistance of a tumor (e.g., breast cancer) to a therapy containing a HER2 -targeted therapy, wherein said combination comprises inavolisib and PH FDC SC (Phesgo). In some embodiments, said combination is administered according to any uses as detailed herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIG 1 shows the study design of a Phase III study of maintenance inavolisib or placebo + pertuzumab + trastuzumab following induction with pertuzumab + trastuzumab + a taxane in patients with PIK3CA-mutated, HER2-positive advanced breast cancer (INAVO122).DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0027] The words "comprise," "comprising," "include," "including," and "includes" when used in this specification and claims are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

[0028] The terms "treat" and "treatment" refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the growth, development or spread of cancer. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.|0029] The phrase "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and / or relieve to some extent one or more of the symptoms associated with the cancer. To the extent the drug may prevent growth and / or kill existing cancer cells, it may be cytostatic and / or cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0030] “Time to progression” or “TTP” refers to the time from randomization until objective tumor progression.

[0031] “Objective response rate” or “ORR” refers to the proportion of patients with a confirmed complete response or partial response on two consecutive occasions > 4 weeks apart, as determined by the investigator according to RECIST vl.l.

[0032] “Best overall response rate” or “BOR” refers to the proportion of patients with a CR or PR, as determined by the investigator according to RECIST vl. l.

[0033] “Duration of response” or “DOR” refers to the time from the first occurrence of a documented objective response to disease progression, as determined by the investigator according to RECIST vl. l, or death from any cause, whichever occurs first.

[0034] “Clinical benefit rate” or “CBR” refers to the proportion of patients with complete response, partial response, and / or stable disease for at least 24 weeks, as determined according to RECIST vl. l.

[0035] “Overall survival” or “OS” refers to the time from enrollment to death from any cause.

[0036] “Time to deterioration (TTD) in pain” refers to the time from randomization to the first documentation of a >2-point increase from baseline on the “worst pain” item from the Brief Pain Inventory-Short Form (BPI-SF).

[0037] “Time to deterioration (TTD) in Physical Function’ refers to the time from randomization to the first documentation of a > 10-point decrease from baseline in the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30) Physical Function scale (items 1-5).|0038] “Time to deterioration (TTD) in Role Function” refers to the time from randomization to the first documentation of a > 10-point decrease from baseline in the EORTC QLQ-C30 Role Function scale (items 6 and 7).|0039] “Time to deterioration (TTD) in global health status (GHS) / health-related quality of life (HRQoL)” refers to the time from randomization to the first documentation of a > 10-point decrease from baseline in the EORTC QLQ-30 GHS / HRQoL scale (items 29 and 30).

[0040] “Progression free survival” or “PFS” refers to the time from enrollment to the date of the first recorded occurrence of disease progression, as determined by the investigator using RECIST vl. l or death from any cause, whichever occurs first.

[0041] “Complete response” or “CR” refers to the disappearance of all target lesions and non-target lesions and (if applicable) normalization of tumor marker level.

[0042] “Partial response”, “PR” or “Non-CR / Non-PrD” refers to persistence of one or more non-target lesions and / or (if applicable) maintenance of tumor marker level above the normal limits. A PR can also refer to > 30% decrease in sum of diameters of target lesions, in the absence of CR, new lesions, and unequivocal progression in non-target lesions.

[0043] “Progressive disease” or “PrD” refers to > 20% increase in sum of diameters of target lesions, unequivocal progression in non-target lesions, and / or appearance of new lesions.

[0044] “Stable disease” or “SD” refers to neither sufficient shrinkage to qualify for CR or PR nor sufficient increase growth of tumor to qualify for PrD.

[0045] An “administration period” or “cycle” refers to a period of time comprising administration of one or more agents described herein and an optional period of time comprising no administration of one or more of the agents described herein. For example, a cycle can be 28 days in total length and include administration of one or more agents for 21 days and a rest period of 7 days. A “rest period” refers to a period of time where at least one of the agents described herein are not administered. In one embodiment, a rest period refers to a period of time where none of the agents described herein are administered. In one embodiment, a cycle does not include any rest period.

[0046] A “dosing regimen” refers to a period of administration of the agents described herein comprising one or more cycles, where each cycle can include administration of the agents described herein at different times or in different amounts.

[0047] “QD” refers to administration of a compound once daily.

[0048] A graded adverse event refers to the severity grading scale as established for by NCI CTCAE. In one embodiment, the adverse event is graded in accordance with the table below.|0049] The term "detection" includes any means of detecting, including direct and indirect detection.

[0050] The term "prognosis" is used herein to refer to the prediction of the likelihood of cancer- attributable death or progression, including, for example, recurrence, metastatic spread, and drug resistance, of a neoplastic disease, such as cancer.]0051] The term "prediction" (and variations such as predicting) is used herein to refer to the likelihood that a patient will respond either favorably or unfavorably to a drug or set of drugs. In one embodiment, the prediction relates to the extent of those responses. In another embodiment, the prediction relates to whether and / or the probability that a patient will survive following treatment, for example treatment with a particular therapeutic agent and / or surgical removal of the primary tumor, and / or chemotherapy for a certain period of time without cancer recurrence. The predictive methods of the invention can be used clinically to make treatment decisions by choosing the most appropriate treatment modalities for any particular patient. The predictive methods of the present invention are valuable tools in predicting if a patient is likely to respond favorably to a treatment regimen, such as a given therapeutic regimen, including for example, administration of a given therapeutic agent or combination, surgical intervention, chemotherapy, etc., or whether long-term survival of the patient, following a therapeutic regimen is likely.

[0052] The term "increased resistance" to a particular therapeutic agent or treatment option, when used in accordance with the invention, means decreased response to a standard dose of the drug or to a standard treatment protocol.

[0053] "Response" can be assessed using any endpoint indicating a benefit to the patient, including, without limitation, (1) inhibition, to some extent, of tumor growth, including slowing down or complete growth arrest; (2) reduction in the number of tumor cells; (3) reduction in tumor size; (4) inhibition (e.g., reduction, slowing down or complete stopping) of tumor cell infiltration into adjacent peripheral organs and / or tissues; (5) inhibition (e.g., reduction, slowing down or complete stopping) of metastasis; (6) enhancement of anti-tumor immune response, which may, but does not have to, result in the regression or rejection of the tumor; (7) relief, to some extent, of one or more symptoms associated with the tumor; (8) increase in the length of survival following treatment; and / or (9) decreased mortality at a given point of time following treatment.

[0054] A “biomarker” is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention. Biomarkers may be of several types: predictive, prognostic, or pharmacodynamics (PD). Predictive biomarkers predict which patients are likely to respond or benefit from a particular therapy. Prognostic biomarkers predict the likely course of the patient’s disease and may guide treatment. Pharmacodynamic biomarkers confirm drug activity, and enables optimization of dose and administration schedule.

[0055] “Change” or “modulation” of the status of a biomarker, including a PIK3CA mutation or set of PIK3CA mutations, as it occurs in vitro or in vivo is detected by analysis of a biological sample using one or more methods commonly employed in establishing pharmacodynamics (PD), including: (1) sequencing the genomic DNA or reverse-transcribed PCR products of the biological sample, whereby one or more mutations are detected; (2) evaluating gene expression levels by quantitation of message level or assessment of copy number; and (3) analysis of proteins by immunohistochemistry (IHC), immunocytochemistry, ELISA, or mass spectrometry whereby degradation, stabilization, or post-translational modifications of the proteins such as phosphorylation or ubiquitination is detected.

[0056] A "chemotherapeutic agent" is a biological (large molecule) or chemical (small molecule) compound useful in the treatment of cancer, regardless of mechanism of action.

[0057] The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and / or warnings concerning the use of such therapeutic products.

[0058] The phrase "pharmaceutically acceptable salt" as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention. Exemplary salts include,but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate “mesylate”, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis -(2- hydroxy-3 -naphthoate)) salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counter ion.

[0059] The desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art. For example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. Acids which are generally considered suitable for the formation of pharmaceutically useful or acceptable salts from basic pharmaceutical compounds are discussed, for example, by 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, 18thed., (1995) Mack Publishing Co., Easton PA; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.

[0060] The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the patient being treated therewith.

[0061] The term "synergistic" as used herein refers to a therapeutic combination which is more effective than the additive effects of the two or more single agents. A determination of asynergistic interaction between a compound of inavolisib or a pharmaceutically acceptable salt thereof, and one or more chemotherapeutic agent may be based on the results obtained from the assays described herein. The results of these assays can be analyzed using the Chou and Talalay combination method and Dose-Effect Analysis with CalcuSyn® software in order 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 utilizing a standard program for quantifying synergism, additivism, and antagonism among anticancer agents described by Chou and Talalay, in "New Avenues in Developmental Cancer Chemotherapy," Academic Press, 1987, Chapter 2. Combination Index values less than 0.8 indicates synergy, values greater than 1.2 indicate antagonism and values between 0.8 and 1.2 indicate additive effects. The combination therapy may provide "synergy" and prove "synergistic", i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., by different injections in separate syringes or in separate pills or tablets. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. Combination effects were evaluated using both the BLISS independence model and the highest single agent (HSA) model (Lehar et al. 2007, Molecular Systems Biology 3:80). BLISS scores quantify degree of potentiation from single agents and a BLISS score > 0 suggests greater than simple additivity. An HSA score > 0 suggests a combination effect greater than the maximum of the single agent responses at corresponding concentrations.

[0062] As used herein, unless otherwise noted, "induction therapy" refers to first-line treatment for advanced breast cancer (ABC) with a taxane, (e.g., paclitaxel, docetaxel or nab-paclitaxel), plus pertuzumab and trastuzumab (PH) or PH FDC SC (Phesgo) as per standard of care (SoC), and "maintenance therapy" refers to subsequent treatment with inavolisib or placebo combined with PH FDC SC (Phesgo) in participants who have not experienced progression of disease after induction treatment.Clinical CompoundsInavolisib:(00631 Inavolisib is a potent, orally bioavailable, clinical-stage, selective inhibitor of the Class I PI3K alpha isoform (PI3Ka), with > 300-fold less potent biochemical inhibition for other Class I PI3K beta, delta, and gamma isoforms and increased potency in tumor cells bearing mutant PI3K over 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-pl 10 alpha 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 ACS National 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 Cancer Symposium, Dec. 5-9 2017, San Antonio, TX, Abstract Publication Number: PD4-14; Edgar, K. et al “Preclinical characterization of GDC-0077, a specific PI3K alpha inhibitor in early clinical development Cancer Research 77(13 Supplement): Abstract 156 • July 2017).[0064| Inavolisib, CAS Registry Number 2060571-02-8, Genentech, Inc., US 9650393; named as (5)-2-((2-((5)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[ / ]imidazo[l,2- t / ][l,4]oxazepin-9-yl)amino)propanamide, has the structure:

[0065] Inavolisib is also known as GDC-0077, RG6114, RO7113755, or chemical name (2S)-2- [[2-[(4S)-4-(Difluoromethyl)-2-oxo-3-oxazolidinyl]-5,6-dihydroimidazo[l,2- d][l,4]benzoxazepin-9-yl]amino]propanamide.

[0066] Inavolisib exerts its activity by binding to the ATP binding site of PI3K, thereby inhibiting the phosphorylation of membrane-bound 4,5-phosphatidylinositol bisphosphate (PIP2) to 3, 4,5-phosphatidylinositol triphosphate (PIP3). Inhibiting the phosphorylation of PIP2 to PIP3 decreases downstream activation of AKT and pS6, resulting in decreased cellular proliferation, metabolism, and angiogenesis. Nonclinical studies demonstrate that inavolisib specificallydegrades mutant pl 10 alpha, inhibits proliferation and induces apoptosis of PIK3CA -mutant breast cancer cell lines, inhibits tumor growth in human breast xenograft models harboring PIK3CA mutations, and reduces downstream PI3K-pathway markers, including phosphorylated form of protein kinase B (pAKT), PRAS40 phosphorylated at Threonine 246 (pPRAS40), and S6RP phosphorylated at Serine 235 / 236 (pS6RP).Trastuzumab:[0067| Trastuzumab (CAS 180288-69-1, HERCEPTIN®, huMAb4D5-8, rhuMAb HER2, Genentech) is a recombinant DNA-derived, IgGl kappa, monoclonal antibody that is a humanized version of a murine anti-HER2 antibody (4D5) that selectively binds with high affinity in a cellbased assay (Kd = 5 nM) to the extracellular domain of HER2 (US 5677171; US 5821337; US 6054297; US 6165464; US 6339142; US 6407213; US 6639055; 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, in both in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpress HER2 (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 cellular cytotoxicity, 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 cancers (Baselga et al, (1996) J. Clin. Oncol. 14:737-744) that have received extensive prior anti-cancer therapy, and has since been used in over 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. T N 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 (Suppl 1): 52). In 2006, the FDA approved HERCEPTIN® (trastuzumab, Genentech Inc.) as part of a treatment regimen containing doxorubicin, cyclophosphamide and paclitaxel for the adjuvant treatment of patients with HER2- positive, node-positive breast cancer.

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

[0070] Pertuzumab (also known as recombinant humanized monoclonal antibody 2C4, rhuMAb 2C4, PERJETA®, Genentech, Inc, South San Francisco) represents the first in a new class of agents known as HER dimerization inhibitors (HD I) and functions 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 Struct Biol 10: 158-9 (2003); Cho et al. Nature 421 :756-60 (2003); and Malik et al. Pro Am Soc Cancer Res 44: 176-7 (2003).

[0071] PERJETA® (pertuzumab) was 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 granted accelerated approval to PERJETA® (pertuzumab) as part of a complete treatment regimen for patients with early stage breast cancer (EBC) before surgery (neoadjuvant setting). PERJETA® is the first FDA-approved drug for the neoadjuvant treatment of breast cancer.

[0072] Pertuzumab inhibits ligand-initiated intracellular signaling through major signal pathways, including PI3K, which can result in cell growth arrest and apoptosis. In addition, Both trastuzumab and pertuzumab mediate antibody-dependent cellular cytotoxicity (ADCC). Overall, the combination of pertuzumab and trastuzumab is well tolerated, without significant increase in left ventricular systolic dysfunction.PH FDC SC (Phesgo):

[0073] PHESGO® (pertuzumab, trastuzumab, and hyaluronidase-zzxf) contains a fixed-dose combination of pertuzumab and trastuzumab with hyaluronidase for injection under the skin, and has been approved by U.S. FDA in 2020 for the treatment of early and metastatic HER2-positive breast cancer. PHESGO can be administered by subcutaneous (SC; under the skin) injection in combination with intravenous (IV) chemotherapy.

[0074] Phesgo is a ready -to-use formulation of PERJETA and HERCEPTIN (PH) coformulated in a single vial for SC injection use with recombinant human PH20 hyaluronidase(rHuPH20). Phesgo administration has been proven equivalent to IV PH from a PK, efficacy, and safety perspective (Tan et al. 2021). Phesgo can be administered in 5-8 minutes versus hours and is preferred by most participants compared to IV administration of PH (O’Shaughnessy et al.2020). Phesgo is the SoC and has received health authority approval in the same settings as the IV formulations: Specifically, Phesgo is approved in the United States and can be administered at home by a health-care professional. Phesgo is also approved in the European Union and in numerous other countries in the world. The indications cover the use in participants with HER2- positive EBC and ABC.

[0075] The Prescribing Information of Phesgo is available at www.gene.com / download / pdf / phesgo_prescribing.pdf, which is incorporated herein by reference in its entirety.Indications and Usage

[0076] PHESGO is a combination of pertuzumab and trastuzumab, HER2 / neu receptor antagonists, and hyaluronidase, an endoglycosidase, indicated for:(1.1) Use in combination with chemotherapy as: (a) neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer; (b) adjuvant treatment of patients with HER2 -positive early breast cancer at high risk of recurrence.(1.2) Use in combination with docetaxel for treatment of patients with HER2positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.Patient Selection

[0077] (2.1) Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens [see Indications and Usage (1) and Clinical Studies (14)]. Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA- approved tests specific for breast cancer by laboratories with demonstrated proficiency.Information on the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: www.fda.gov / CompanionDiagnostics. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.Recommended Doses and Schedules[0078J (2.3) The recommended dosage and administration schedule for PHESGO are as follows:Initial dose: 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase in 15 mL (1,200 mg, 600 mg, and 30,000 units / 15 mL); Administer subcutaneously over approximately 8 minutes.Maintenance dose (administer every 3 weeks): 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase in 10 mL (600 mg, 600 mg, and 20,000 units / 10 mL); Administer subcutaneously over approximately 5 minutes every 3 weeks.

[0079] No dose adjustments for PHESGO are required for patient body weight or for concomitant chemotherapy regimen.

[0080] Patients currently receiving intravenous pertuzumab and trastuzumab can transition to PHESGO. In patients receiving intravenous pertuzumab and trastuzumab with < 6 weeks since their last dose, administer PHESGO as a maintenance dose of 600 mg pertuzumab / 600 mg trastuzumab and every 3 weeks for subsequent administrations. In patients receiving intravenous pertuzumab and trastuzumab with > 6 weeks since their last dose, administer PHESGO as 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 administrations.

[0081] Neoadjuvant Treatment of Breast Cancer'. Administer PHESGO every 3 weeks for 3 to 6 cycles as part of a treatment regimen for early breast cancer [see Clinical Studies (14.2)]. Refer to the prescribing information for pertuzumab, administered in combination with trastuzumab and chemotherapy, for recommended dose and dosage modifications. Following surgery, patients should continue to receive PHESGO to complete 1 year of treatment (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first, as a part of a complete regimen for early breast cancer.

[0082] Adjuvant Treatment of Breast Cancer'. Administer PHESGO every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first, as part of a complete regimen for early breast cancer, including standard anthracycline- and / or taxane-based chemotherapy. Start PHESGO on Day 1 of the first taxane-containing cycle [see Clinical Studies (14.2)].

[0083] Metastatic Breast Cancer (MBC): When administered with PHESGO, the recommended initial dose of docetaxel is 75 mg / m2 administered as an intravenous infusion. The dose may be escalated to 100 mg / m2 administered every 3 weeks if the initial dose is well tolerated.Administer PHESGO until disease progression or unmanageable toxicity, whichever occurs first.Description of PHESGO

[0084] PHESGO is a combination of pertuzumab, trastuzumab, and hyaluronidase.

[0085] Pertuzumab is a recombinant humanized monoclonal antibody that targets the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein (HER2). Pertuzumab is produced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary) culture. Pertuzumab has an approximate molecular weight of 148 kDa.

[0086] Trastuzumab is a humanized IgGl kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2. Trastuzumab is produced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary) culture. Trastuzumab has a molecular weight of approximately 148 kDa.

[0087] Hyaluronidase (recombinant human) is an endoglycosidase used to increase 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 for a soluble fragment of human hyaluronidase (PH20). Hyaluronidase (recombinant human) has a molecular weight of approximately 61 kDa.

[0088] PHESGO (pertuzumab, trastuzumab, and hyaluronidase-zzxf) injection is a sterile, preservative-free, clear to opalescent, and colorless to slightly brownish solution in single-dose vials for subcutaneous administration supplied as each carton containing one single-dose vial:(a) 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase / 15 mL (80 mg, 40 mg, and 2,000 units / mL). In this configuratiuon, PHESGO is supplied in a 15 mL singledose vial containing 1,200 mg of pertuzumab, 600 mg of trastuzumab, and 30,000 units of hyaluronidase, and a,a-trehalose (397 mg), L-histidine (6.75 mg), L-histidine hydrochloric monohydrate (53.7 mg), L-methionine (22.4 mg), polysorbate 20 (6 mg), and sucrose (685 mg) with a pH of 5.5.(b) 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase / 10 mL (60 mg, 60 mg, 2,000 units / mL). In this configuration, PHESGO is supplied in a 10 mL single-dose vial containing 600 mg of pertuzumab, 600 mg of trastuzumab, and 20,000 units of hyaluronidase, and a,a-trehalose (397 mg), L-histidine (4.4 mg), L-histidine hydrochloric monohydrate (36.1 mg), L-methionine (14.9 mg), polysorbate 20 (4 mg), and sucrose (342 mg) with a pH of 5.5.

[0089] Further details of Phesgo are described in US 2021 / 0403599 Al, incorporated herein by reference.Fulvestrant:

[0090] Fulvestrant is an ER antagonist and an effective treatment for postmenopausal patients with HR+ breast cancer that is relatively well tolerated. The expected toxicities for inavolisib and fulvestrant are not overlapping. It is important to test inavolisib in combination with both letrozole and fulvestrant, as these endocrine therapies have different mechanisms of action, different PK properties, and different potential for drug-drug interactions (DDIs) with inavolisib. [0091 J Fulvestrant (FASLODEX®, AstraZeneca, CAS Reg. No. 129453-61-8) is approved by the FDA for treatment of hormone receptor-positive (HR+) metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy (Kansra (2005) Mol Cell Endocrinol 239(l-2):27-36; Flemming et al (2009) Breast Cancer Res Treat.May;l 15(2):255-68; Valachis et al (2010) Crit Rev Oncol Hematol. Mar; 73 (3): 220-7). Fulvestrant is an estrogen receptor (ER) antagonist with no agonist effects, which works both by down-regulating and by degrading the estrogen receptor (Croxtall (2011) Drugs 71(3):363-380). Fulvestrant is also a selective estrogen receptor down-regulator (SERD).

[0092] Fulvestrant is named as (7a,17P)-7-{9-[(4,4,5,5,5- pentafluoropentyl)sulfmyl]nonyl}estra-l,3,5(10)-triene-3,17-diol and has the structure:

[0093] Fulvestrant belongs to a class of reversible steroidal ER antagonists that directly competes with estrogen for ER binding and is devoid of the partial agonist properties of tamoxifen. Upon binding to ER, it blocks estrogen signaling and increases the degradation of ER protein. The affinity of fulvestrant for the ER is approximately 100-fold greater than that of 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 MBC in postmenopausal women with disease progression following anti-estrogen therapy. In multicenter Phase III studies, fulvestrant was found to be at least equivalent to anastrozole (a non-steroidal Al) in the second-line setting (Howell et al. (2002) J Clin Oncol 20:3396-3403; Osborne CK, et al (2002) J Clin Oncol 20:3386-95). Fulvestrant is also as active as tamoxifen for the first-line treatment of advanced breast cancer (Howell et al. (2004) J Clin Oncol 22: 1605-1613) and displays a level of activity in patients in the post-AI metastatic disease setting similar to that of thenon-steroidal Al exemestane (Chia et al. (2008) J Clin Oncol 26: 1664-1670). High-dose fulvestrant (500 mg once monthly) has been demonstrated to be at least as effective as anastrozole in terms of clinical benefit rate (CBR) and overall response rate and to be associated with significantly longer time to progression for the first-line treatment of women with advanced HRpositive breast cancer (Robertson et al. (2009) J Clin Oncol 27:4530-4535). High-dose fulvestrant recently demonstrated superior progression-free survival (PFS) in women with ERpositive advanced breast cancer treated with 500 mg versus patients 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 fewer estrogenic effects than did tamoxifen and resulted in less arthralgia than did the Al anastrozole (Osborne et al. (2002) J Clin Oncol 20:3386-3395). These results led to the approval of 500 mg fulvestrant given once a month as the currently approved recommended dose in the United States and the European Union (in 2010) for postmenopausal women whose disease has spread after treatment with an Al. These studies demonstrate that fulvestrant is an important treatment option for patients with advanced breast cancer and, as such, is considered appropriate control therapy for the present study.Letrozole:

[0094] Letrozole is an effective treatment for postmenopausal patients with HR+ breast cancer that is relatively well tolerated. The expected toxicities for inavolisib and letrozole are not overlapping. Letrozole (FEMARA®, Novartis Pharm.) is an oral non-steroidal aromatase inhibitor for the treatment of hormonally-responsive breast cancer after surgery (Bhatnagar et al (1990) J. Steroid Biochem. andMol. Biol. 37: 1021; Lipton et al (1995) Cancer 75:2132; Goss, P.E. and Smith, R.E. (2002) Expert Rev. Anticancer Ther. 2:249-260; Lang et al (1993) The Journal of Steroid Biochem. andMol. Biol. 44 (4-6):421-8; EP 236940; US 4978672). FEMARA® is approved by the FDA for the treatment of local or metastatic breast cancer that is hormone receptor positive (HR+) or has an unknown receptor status in postmenopausal women. [00951 Letrozole is named as 4,4'-((lH-l,2,4-triazol-l-yl)methylene)dibenzonitrile (CAS Reg. No. 112809-51-5), and has the structure:Paclitaxel:

[0096] Paclitaxel is a chemotherapy medication approved for the treatment of a number of types of cancers (for example, ovarian cancer, breast cancer, lung cancer, etc.), as a monotherapy or in combination with other anti-cancer agents. Paclitaxel is named as 5P,20-Epoxy- l,2a,4,7p,10p,13a-hexahydroxytax-l l-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)- N-benzoyl-3-phenylisoserine, and has the structure:Combination Therapy[0097J In human epidermal growth factor receptor 2-positive (HER2+) breast cancer, dysregulation of the PI3K / AKT / mT0R pathway, in the form of activating mutations and other aberrations, has been identified as a possible mechanism of resistance to HER2 -targeted therapies. As such, continuous inhibition of the HER2 pathway, along with co-targeting of the PI3K / AKT / mTOR pathway, may restore sensitivity to HER2 -targeted therapies. Addition of a PI3K inhibitor to trastuzumab and pertuzumab may improve outcomes for patients with PIK3CA- mutant HER2+ breast cancer.

[0098] Provided herein are combinations or combination therapies comprising inavolisib and fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC or Phesgo). In some embodiments, the combination therapy comprises 9 mg of invalisib administered orally dailly (PO, QD) and 600 mg pertuzumab, 600 mg trastuzumab, and recombinant human PH20 hyaluronidase (rHuPH20) administered subcutaneously every three weeks (SC, Q3W).

[0099] The combinations or combination therapies described herein can be provided as a kit comprising one or more of the agents for administration. In one embodiment, the kit includes inavolisib and Phesgo. In one embodiment, the kit includes inavolisib, pertuzumab, trastuzumab, and hyaluronidase-zzxf. In one embodiment, the kit includes inavolisib, pertuzumab, trastuzumab, and rHuPH20. In one embodiment, the kit includes 9-mg oral tablets of invalosib and a maintenance dose of PH FDC SC (Phesgo) comprising 600 mg pertuzumab, 600 mg trastuzumab and rHuPH20 SC for injection. In one embodiment, the kit may further include aloading dose of PH FDC SC (Phesgo) comprising 1200 mg pertuzumab, 600 mg trastuzumab and rHuPH20 SC for injection. In one embodiment, the agents of the combination or combination therapy described herein are supplied in a kit in a form ready for administration. Kits described herein can include instructions such as package inserts. In one embodiment, the instructions are package inserts - one for each agent in the kit.

[0100] Further provided are kits for carrying out the methods detailed herein, which comprises a phamaceutical composition or a combination therapy described herein and instructions for use in the treatment of breast cancer.

[0101] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any phamaceutical composition described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit. One or more components of a kit may be sterile and / or may be contained within sterile packaging.Methods

[0102] HER2 overexpression is an important prognostic and predictive biomarker in metastatic breast cancer (Pauletti et al. 2000). In the phase III study of trastuzumab plus docetaxel with or without pertuzumab in patients with IL HER2+ mBC, above-median (high) HER2 protein expression by immunohistochemistry and above-median (high) HER2 mRNA expression 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 are also observed in patients with HER2 expression, and there are differences in prevalence of PIK3CA mutations. PIK3CA mutations are observed in nearly twice the number of patients whose tumors had focal, heterogeneous HER2 expression (42%) relative to the number of patients whose tumors had robust homogenous HER2 expression (24%) by IHC (Perez et al. 2019). Thus it is beneficial to treat HER2+ breast cancer with a combination of a mutant PI3Ka inhibitor and a HER2 -targeted therapy.

[0103] All PI3Ka inhibitors are not equal. Inavolisib is especially advantageous in inhibiting growth of HER2+ PIK3CA-mutant cancer cells over another clinically relevant PI3Ka inhibitor alpelisib (a.k.a. BYL719). In a study comparing efficacy of inavolisib with alpelisib, the results showed a significant difference between the sensitivity of inavolisib and alpelisib in HER2- amplified (~20-fold difference between the mean IC50 values) versus HER2-negative cell lines(6-fold difference between two inhibitors). Both inhibitors were not differentiated in PIK3CA- WT cell lines regardless of HER2 status.

[0104] Provided herein are methods of treating HER2 positive cancer. In one embodiment, the method comprises treating HER2-positive breast cancer in a patient having locally advanced or metastatic PIK3CA-mutated HER2 -positive breast cancer, by administering to the patient a combination therapy that includes inavolisib and a HER2 -targeted therapy such as PH FDC SC (Phesgo). The combination therapy is administered as a maintenance therapy after the patient has received an induction therapy including a taxane-based chemotherapy (e.g., paclitaxel, docetaxel or nab-paclitaxel) and pertuzumab and trastuzumab (PH) or PH FDC SC (Phesgo). The choice of the SC formulation of PH versus IV enhances the flexibility of care and improve patients’ experience.

[0105] Also provided are methods of treating locally advanced or metastatic PIK3CA-mutated (or PIK3CA mutant) HER2-positive breast cancer in a patient comprising administering a therapeutically effective amount of inavolisib, or a pharmaceutically acceptable salt thereof, and PH FDC SC (Phesgo).

[0106] In some embodiments, provided is 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: inavolisib and PH FDC SC (Phesgo); wherein said combination therapy is administered over a 21 -day cycle.

[0107] In some embodiments, provided is 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. administering inavolisib QD on days 1-21 of a first 21 -day cycle; and b. administering PH FDC SC (Phesgo) on day 1 of a first 21-day cycle.

[0108] In some of these embodiments, the method further comprises one or more additional 21- day cycles comprising: a. administering inavolisib on days 1-21 of each additional 21-day cycle; and b. administering PH FDC SC (Phesgo) on day 1 of each additional 21-day cycle.

[0109] In some embodiments, the patient receives an induction therapy comprising administering pertuzumab and trastuzumab (Perjeta and Herceptin, or PH) and a taxane-based chemotherapy prior to administering the combination therapy comprising inavolisib and PH FDC SC. In some embodiments, the induction therapy comprises administering PH FDC SC and a taxane-based chemotherapy (e.g., paclitaxel, docetaxel or nab-paclitaxel). In some embodiments,the induction therapy comprises a dosing regimen comprising four (4) to eight (8) (e.g., 4, 5, 6 or 8) 21 -day cycles of (a) administering PH FDC SC on day 1 of each 21 -day cycle; and (b) administering paclitaxel on days 1, 8 and 15 of each 21 -day cycle. In some embodiments, the induction therapy comprises a dosing regimen comprising four (4) to eight (8) 21 -day cycles of (a) administering PH FDC SC on day 1 of each 21 -day cycle; and (b) administering a taxane- based chemotherapy per SoC (e.g., administering docetaxel or nab-paclitaxel on day 1 of each 21- day cycle).

[0110] In some embodiments, the patient is treated with a maintence therapy after the induction therapy, the maintence therapy comprising inavolisib and PH FDC SC (Phesgo).

[0111] In some embodiments, provided is 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 an induction therapy followed by a maintenace therapy. In some embodiments, the induction therapy comprises a dosing regimen comprising 4 to 8 21 -day cycles of administering PH FDC SC (Phesgo) on Day 1 of each 21 -day cycle and administering a taxane-based chemotherapy in accordance with its prescribing information (e.g., administering paclitaxel on days 1, 8 and 15 of each 21 -day cycle, or administering docetaxel or nab-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 of administering inavolisib on days 1-21 of each 21 -day cycle and administering PH FDC SC (Phesgo) on Day 1 of each 21 -day cycle.

[0112] In some embodiments, the induction therapy comprises a dosing regimen comprising four to eight 21 -day cycles of administering PH FDC SC (Phesgo) comprising 600 mg pertuzumab, 600 mg trastuzumab, and rHuPH20 SC on Day 1 of each 21 -day cycle, and administering a taxane-based chemotheray according to its prescibing information, e.g., administering paclitaxel weekly on Days 1, 8 and 15 of each 21 -day cycle, or administering docetaxel or nab-paclitaxel on day 1 of each 21 -day cycle. In some embodiments, the induction therapy may further comprise administering a loading dose of PH FDC SC (Phesgo) comprising 1200 mg pertuzumab, 600 mg trastuzumab, and rHuPH20 SC on Day 1 of the first 21 -day cycle.

[0113] In some embodiments, the maintenance therapy comprises a dosing regimen comprising one or more 21-day cycles of administering 9 mg inavolisib (e.g., in an oral tablet) on days 1-21 of each 21-day cycle and administering PH FDC SC (Phesgo) comprising 600 mg pertuzumab, 600 mg trastuzumab, and rHuPH20 SC on Day 1 of each 21-day cycle. In some embodiments, in case the patient misses a dose of Phesgo for any cycle and the time between doses is > 6 weeks, areloading dose of PH FDC SC (Phesgo) (1200 mg pertuzumab, 600 mg trastuzumab, and rHuPH20 SC) is given.

[0114] Depending on dose-limiting toxicides (DLTs) observed in the patient, inavolisib may be administered on a 6 / 1 or 5 / 2 dosing regimen. Inavolisib is given for 6 days in a week with 1 day off, or 5 days in a week with 2 days off.

[0115] In some embodiments, provided is 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 maintenace therapy comprising a dosing regimen comprising: a. administering inavolisib on days 2-7, 9-14 and 16-21 of each 21-day cycle; and b. administering PH FDC SC (Phesgo)on day 1 of each 21-day cycle.

[0116] In some embodiments, provided is 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 maintenace therapy comprising a dosing regimen comprising: a. administering inavolisib on days 3-7, 10-14 and 17-21 of each 21-day cycle; and b. administering PH FDC SC (Phesgo) on day 1 of each 21-day cycle.

[0117] After receiving 4 to 8 cycles of an induction therapy comprising PH FDC SC (Phesgo) and a taxane-based chemotherapy (e.g., paclitaxel, docetaxel or nab -paclitaxel), the patient may continue receiving one or more cycles of the maintenance therapy comprising inavolisib and PH FDC SC (Phesgo) until disease progression or unacceptable related toxicity. During maintenance therapy, patients with HR-positive / HER2-positive metastatic breast cancer may be treated with an endocrine therapy e.g., fulvestrant or an aromatase inhibitor such as letrozole).

[0118] In one embodiment, the method includes a combination therapy comprising inavolisib and PH FDC SC (Phesgo). In one embodiment, the method includes a maintenace therapy comprising inavolisib and PH FDC SC (Phesgo) in accordance with a dosing regimen described herein. In one embodiment, the method includes an induction therapy comprising PH FDC SC (Phesgo) and a taxane-based chemotherapy (e.g., paclitaxel, docetaxel or nab-paclitaxel) administered in accordance with a dosing regimen described herein.

[0119] In a further aspect, provided is a method of inhibiting tumor growth or producing / increasing tumor regression in a patient having locally advanced or metastatic PIK3CA-mutant HER2 -positive breast cancer, the method comprising administering to the patient a combination therapy according to the methods detailed herein.

[0120] Agents described herein can be administered in accordance with a package insert. In one embodiment of the methods described herein, agents can be administered in an effective amount as described herein. Agents in a combination therapy detailed herein may be administered simultaneously or sequentially. In one embodiment, inavolisib is administered before or after PH FDC SC (Phesgo).

[0121] In some embodiments, inavolisib is administered at an amount of 3, 6 or 9 mg, e.g., in one or more oral tablets. In some embodiments, inavolisib is adminstered orally at a 9 mg daily dose. In some of these embodiments, inavolisib is administered at an amount of 9 mg, e.g., in an oral tablet. In some embodiments, inavolisib is adminstered orally at a 6 mg daily dose, e.g., in one or more oral tablets.

[0122] In some embodiments of the induction therapy, paclitaxel is administered by intravenous (IV) infusion. In some embodiments, paclitaxel is administered at a weekly dose of 80 mg / m2. In some embodiments, paclitaxel is administered by intravenous infusion at a dose of 80 mg / m2per week.

[0123] In one embodiment, the methods described herein include a combination therapy described herein administered according to a dosing regimen comprising one 21 -day cycle. In another embodiment, the methods described herein include a combination therapy described herein administered according to a dosing regimen comprising a first 21 -day cycle followed by additional 21 -day cycles. In another embodiment, the methods described herein include a maintenance therapy described herein administered according to a dosing regimen comprising a first 21-day cycle followed by 2 to 30 additional 21-day cycles, or until disease progression or unacceptable toxicity. In yet another embodiment, the methods described herein include an induction therapy described herein administered according to a dosing regimen comprising a first 21-day cycle followed by up to seven additional 21-day cycles, or until disease progression or unacceptable toxicity. In another embodiment, the methods described herein include an induction therapy described herein administered according to a dosing regimen comprising a first 21-day cycle followed by three to seven additional 21-day cycles, and a maintence therapy described herein administered according to a dosing regimen comprising one or more 21-day cycles (e.g., up to 30 additional 21-day cycles), or until disease progression or unacceptable toxicity.

[0124] The the efficacy of the combination is measured as a function of progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and other relevant clinical outcome.

[0125] In some embodiments, the patient has PIK3CA mutant, HER2 positive, locally advanced or metastatic breast cancer. In some embodiments, the patient is a female patient withhistologically documented locally advanced or metastatic PIK3CA-mutant HER2+ breast cancer. The hormone receptor status of the patient may be positive or negative. In some embodiments, the patient has hormone receptor positive (HR+), locally advanced or metastatic PIK3CA-mutated HER2-positive breast cancer. In some embodiments, the patient has hormone receptor nagative (HR-), locally advanced or metastatic PIK3CA-mutated HER2-positive breast cancer.

[0126] In some embodiments, the patient has mutant PIK3CA having mutations 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 mutant PIK3CA having mutations at one or more of H1047, E545, E542, Q546, N345, C420, M1043, G1049, E453, KI 11, G106, G118, and R88. In some embodiments, the patient has mutant 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, M I 043I / T / V, G1049A / C / D / R / S, E453A / D / G / K / Q / V, KI 11N / R / E, G106A / D / R / S / V, G118D, and R88Q. In some embodiments, the patient has 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 H I 047D / 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, M I 043I / 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.

[0127] In some embodiments, the patient has mutant 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 a double mutation 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.[0128[ PIK3CA-mutant tumor status can be assessed by either central testing of blood or local testing of blood or tumor tissue. In some embodiments, the central test for identification of eligible PIK3CA mutations is the FoundationOne Liquid Clinical Trial Assay performed at Foundation Medicine, Inc. In some embodiments, the local tests of blood or tumor tissue isperformed using a Sponsor pre-approved PCR- or NGS-based assay at a CLIA-certified or equivalent laboratory.

[0129] The HER2 status of tumors may be assessed by HER2 protein overexpression and / or HER2 gene amplification in tumor specimens using known methods, for example, FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification, preferably performed using FDA-approved tests specific for breast cancer by laboratories with demonstrated proficiency. HER2+ is defined as (i) a HER2 IHC score of 3+; (ii) a HER2 IHC score of 2+ accompanied by a dual-probe ISH HER2 / CEP17 ratio of > 2.0 (preferred); (iii) a fluorescence, chromogenic, or silver ISH test indicating the presence of HER2 gene amplification; or (iv) HER2+ per local clinical guidelines.[01301 In some embodiments, the patient is a female patient with histologically documented locally advanced or metastatic PIK3CA-mutant HER2+ breast cancer. In some embodiments, the patient has a HER2 IHC score of 3 or above. In some embodiments, the patient has a HER2 IHC score of 2 or above accompanied by a dual-probe ISH HER2 / CEP17 ratio of no less than 2.0 (preferred). In some embodiments, the patient has a fluorescence, chromogenic, or silver ISH test indicating the presence of HER2 gene amplification;. In some embodiments, the patient is HER2+ per local clinical guidelines. In some embodiments, the patient has a fasting glucose level at or below 140 mg / dL. In some embodiments, the patient has a glycosylated hemoglobin (HbAic) level below 7%. In some embodiments, the patient has left ventricular ejection fraction (LVEF) > 50%. LVEF can be determined by either echocardiography (ECHO) (preferred) or multiple-gated acquisition (MUGA) scan. In some embodiments, the patient has received a prior HER2 -targeted therapy (e.g., trastuzumab and / or pertuzumab) and not have discontinued the prior HER2 -targeted therapy (e.g., trastuzumab and / or pertuzumab) because of a toxicity assessed as related to the prior HER2 -targeted therapy (e.g., trastuzumab and / or pertuzumab).[01311 Patients may have HR+ or HR- breast cancer. HR+ is defined as expression of ER in > 1% of cells, or HR+ by local clinical guidelines. HR- is defined as expression of ER in < 1% of cells, or HR- by local clinical guidelines. Patients with HR+ breast cancer may be treated with endocrine therapy (e.g., letrozole or fulvestrant), and pre- or perimenopausal patients may also be treated with LHRH agonist therapy, at the investigator’s discretion.

[0132] In some embodiments, the patient has HR+, locally advanced or metastatic PIK3CA- mutant HER2+ breast cancer, and the method of treatment comprises administering to the patient a combination therapy comprising: inavolisib and PH FDC SC (Phesgo), and an endocrine therapy (e.g., fulvestrant or an aromatase inhibitor such as letrozole).

[0133] In some embodiments, provided is a method for treating HR+, locally advanced or metastatic PIK3CA-mutant HER2+ breast cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of inavolisib, or a pharmaceutically acceptable salt thereof, PH FDC SC (Phesgo), and an endocrine therapy (e.g., letrozole or fulvestrant). In some embodiments, the endocrine therapy is letrozole administered in accordance with its approved label, for example, administered daily at a dose of 2.5 mg in an oral tablet). In some embodiments, the endocrine therapy is fulvestrant administered in accordance with its approved label, for example, administered once approximately every four weeks at a dose of 500 mg by intramuscular (IM) infusion.

[0134] In one embodiment of the methods described herein, a patient has been treated with one or more cancer therapies before administration of a combination therapy described herein. In one embodiment of the methods described herein, the prior therapy comprises a HER2 -targeted therapy (e.g., trastuzumab, pertuzumab, or a combination of trastuzumab and pertuzumab). In another embodiment, a patient described herein has not been prior treated with a HER2 -targeted therapy (e.g., trastuzumab, pertuzumab, or a combination of trastuzumab and pertuzumab).

[0135] In one embodiment of the methods described herein, a patient has breast cancer described herein that is resistant to one or more cancer therapies (e.g., a HER2 -targeted therapy such as trastuzumab or pertuzumab). In one embodiment of the methods described herein, resistance to cancer therapy includes recurrence of cancer or refractory cancer. Recurrence may refer to the reappearance of cancer, in the original site or a new site, after treatment. In one embodiment of the methods described herein, resistance to a cancer therapy includes progression of the cancer during treatment with the anti-cancer therapy. In some embodiments of the methods described herein, resistance to a cancer therapy includes cancer that does not response to treatment. The cancer may be resistant at the beginning of treatment or it may become resistant during treatment. In some embodiments of the methods described herein, the cancer is at early stage or at late stage.

[0136] Co-administration of inavolisib with PH FDC SC (Phesgo) may prevent or delay development of resistance of a tumor (e.g., breast cancer) to a HER2 -targeted therapy (e.g., trastuzumab, pertuzumab, or a combination of trastuzumab and pertuzumab). Thus provided is a method of preventing or delaying development of resistance of a tumor (e.g., breast cancer) to a therapy containing a HER2 -targeted therapy (e.g., trastuzumab, pertuzumab, or a combination of trastuzumab and pertuzumab), comprising administering a combination therapy detailed herein. In some embodiments, provided is a method of preventing or delaying development of resistance of a tumor (e.g., breast cancer) to a therapy containing trastuzumab and / or pertuzumab,comprising administering a combination therapy comprising trastuzumab and / or pertuzumab, or a combination therapy comprising inavolisib, trastuzumab and pertuzumab. In some embodiments, the combination therapy is administered according to any methods as detailed herein.Biomarkers

[0137] Breast cancer is a heterogeneous disease with many distinct subtypes as defined by molecular signatures and a diverse array of mutational profiles. In one embodiment, a patient can be tested for PIK3CA / AKTl / PTEN-alteration status. In one embodiment, a patient described herein can be tested for one or more of a phosphatase and tensin homolog (PTEN) mutation, loss of PTEN expression, a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, a protein kinase B alpha (AKT1) mutation, or a combination thereof. In one embodiment, the loss of PTEN expression is hemizygous or homozygous. In another embodiment, samples of patients described herein can be assessed for additional biomarkers in an effort to identify factors that may correlate with the safety and efficacy of the study treatments.

[0138] In one embodiment of the methods described herein, NGS, whole genome sequencing (WGS), other methods, or a combination thereof can be used for DNA obtained from blood samples and tumor tissue from patients described herein. Such samples may be analyzed to identify germline (e.g., BRCA1 / 2) and somatic alterations that are predictive of response to study drug, are associated with progression to a more severe disease state, are associated with acquired resistance to study drug, or can increase the knowledge and understanding of disease biology. In another embodiment of the methods described herein, patients described herein can have cancer characterized by activation of PI3K / Akt signaling such as activating mutations in PIK3CA or AKT1 as well as through alterations in PTEN, such as those provided herein. In another embodiment, PIK3CA / AKTl / PTEN-altered tumor status will be determined using an NGS assay (e.g., Foundation Medicine, Inc. [FMI]). Review of PIK3CA / AKT1 / PTEN -altered status in archival tissue and response measures can be performed on an ongoing basis. Expression of biomarkers (e.g. PTEN) as provided herein can be measured using techniques known in the art such as, for example, immunohistochemistry (IHC).

[0139] Circulating tumor DNA (ctDNA) can be detected in the blood of cancer patients with epithelial cancers and may have diagnostic and therapeutic significance (Schwarzenbach et al. Nat Rev Cancer 2011; 11 :426-437). For example, the mutational status of tumor cells may be obtained through the isolation of ctDNA (Maheswaran S, et al. N Engl J Med 2008; 359:366-77), and ctDNA has been used to monitor treatment effectiveness in melanoma (Shinozaki M, et al. Clin Cancer Res 2007; 13:2068-74). Blood samples from patients described herein can becollected at screening, at time of first tumor assessment, and / or at the study completion / early termination visit. In one embodiment, the samples are used to evaluate oncogenic genetic alterations at baseline and to assess for the possible emergence of new alteration after treatment with inavolisib and a HER2 -targeted therapy.EXAMPLESAbbreviations:AEs, adverse events;AUCo-24, area under the concentration-time curve at 0-24 hours;BMP body mass index;CDK4 / 6i, cyclin-dependent kinase 4 / 6 inhibitor;CI, confidence interval;Cmax, maximum serum concentration;CR, complete response; ctDNA: circulating tumor DNA;D, day;ECOG, Eastern Cooperative Oncology Group;GMR, geometric mean ratio;HbAlc, glycated haemoglobin;HER2, human epidermal growth factor receptor 2;MAF, mutant allele frequency;MBC, metastatic breast cancer;MTD, maximum tolerated dose;NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events;PD, pharmacodynamics;PrD, progressive disease;PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha;PK, pharmacokinetics;PR, partial response; pts: patientsRECIST, Response Evaluation Criteria in Solid Tumors;SD, stable disease;SLD, sum of longest diameters;TRAEs, treatment-related adverse events.Example 1 A Phase III, multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of inavolisib in combination with Phesgo versus placebo in combination with Phesgo as maintenance therapy after first line induction therapy in participants with PIK3CA-mutated HER2-positive locally advanced or metastatic breast cancer|0140] A Phase III study is underway to evaluate the efficacy and safety of inavolisib in combination with PH FDC SC (Phesgo®; pertuzumab, trastuzumab, and rHuPH20 injection for subcutaneous use) versus placebo in combination with PH FDC SC, as a maintenance therapy, after a first line induction therapy in patients with PIK3CA -mutated, HER2+, unresectable LA / mBC.

[0141] A study design diagram is shown in FIG 1. Eligible patients are enrolled for: first-line induction treatment if they are receiving / will receive PH + a taxane, followed by maintenance treatment, or for maintenance treatment if they completed induction treatment off-study. In the maintenance phase, patients are randomized 1 : 1 to receive either inavolisib, 9 mg orally once daily on Days 1-21 of 21 -day cycles + PH FDC SC (Phesgo) (once every 3 weeks), or placebo + PH FDC SC (Phesgo).

[0142] The induction therapy includes PH FDC SC (Phesgo) plus a taxane-based chemotherapy (e.g., paclitaxel, docetaxel or nab-paclitaxel). During the induction therapy phase, PH FDC SC (Phesgo) is administered to participants subcutaneously every 3 weeks (Q3W) on DI of each 21- day cycle, and the investigator's choice of taxane-based chemotherapy is administered after PH FDC SC (Phesgo).

[0143] The maintenance therapy includes inavolisib plus PH FDC SC (Phesgo). During the maintenance phase, Participants receive an inavolisib tablet to betaken orally (PO), once a day (QD), on Days 1-21 of each 21 -day cycle, beginning on Day (D) 1 of Cycle (C) 1 of the treatment, and PH FDC SC (Phesgo) is administered to participants subcutaneously every 3 weeks (Q3W) on DI of each 21-day cycle. An optional endocrine therapy (ET) of investigator's choice is allowed at the discretion of the investigator, based on the standard of care. Allowed ETs are tamoxifen, or one of the specified third-generation aromatase inhibitor (Al [anastrozole, letrozole, orexemestane]), or fulvestrant. The investigator determines and supplies the appropriate luteinizinghormone-releasing hormone (LHRH) agonist locally approved for use in breast cancer. The LHRH agonist is administered according to local prescribing information.

[0144] In the comparator arm of the maintenance phase, participants are administered placebo plus PH FDC SC (Phesgo). An inavolisib-matching tablet is taken PO QD on Days 1-21 of each21 -day cycle, beginning on DI Cl of the maintenance treatment; and PH FDC SC (Phesgo) is administered to participants subcutaneously every 3 weeks (Q3W) on DI of each 21 -day cycle. Optional endocrine therapy (ET) is allowed at the discretion of the investigator, based on the standard of care. Allowed ETs are tamoxifen, or one of the specified third-generation aromatase inhibitor (Al [anastrozole, letrozole, orexemestane]), or fulvestrant. The investigator determines and supplies the appropriate luteinizing hormone-releasing hormone (LHRH) agonist locally approved for use in breast cancer. The LHRH agonist is administered according tolocal prescribing information.

[0145] The primary endpoint analysis utilizes a two-sided stratified log-rank test at a two-sided significance level of 5%. A stratified Cox proportional hazards model is used to estimate the hazard ratio between the two treatment arms and its 95% confidence interval.

[0146] Stratification factors include (i) De novo HER2+ unresectable LA / metastatic vs. recurrent disease, (ii) HR+ vs. HR- tumor status, and (iii) Objective response after induction therapy: PR / CR vs. SD (or non CR / non disease progression for patients with non-measurable disease).

[0147] The primary endpoint of the study includes investigator-assessed progression-free survival (PFS), defined as the time from randomization to the first occurrence of disease progression (per Response Evaluation Criteria in Solid Tumours [RECIST] vl.l), or death from any cause (whichever occurs first). [Time Frame: Up to approximately 40months]

[0148] The secondary endpoints of the study include:(i) overall survival (OS) [ Time Frame: Up to approximately 111 months ],(ii) investigator-assessed objective response rate (ORR) [Time Frame: Up to approximately l l lmonths],(iii) investigator-assessed duration of response (DOR) [Time Frame: Up to approximately l l lmonths],(iv) investigator-assessed clinical benefit rate (CBR) [Time Frame: Up to approximately 111 months],(v) investigator-assessed time to second disease progression (PFS2) [Time Frame: Up to approximately 111 months],(vi) patient-reported outcomes / health-related quality of life (HRQoL) [Time Frame: Day 1 of Cycles 1 and 2 and beyond, 30-day safety follow up visit, post-treatment tumor assessment follow-up with PRO collection and survival follow up visit every 6months (up to 111 months). Each cycle is 21 days.];(vii) Percentage of participants with Adverse Events (Safety) [Time Frame: Day 1 until30 days after the finaldose of study treatment (up to approximately 111 months). Each cycle is 21 days.] and(viii) Plasma concentration of inavolisib at specified timepoints (Pharmacokinetics)[Time Frame: Day 1 of Cycles 1 and 4. Each cycle is 21 days.]

[0149] Key inclusion criteria:1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;2. Centrally confirmed HER2+, PIK3CA-mutated disease;3. Documented HR status per local assessment;4. Histologically or cytologically confirmed LA / mBC not amenable to curative resection;5. Disease-free interval of >6 months from completion of adjuvant or neoadjuvant systemic non-hormonal treatment to recurrence;6. Asymptomatic CNS metastases or CNS metastases controlled with anti-seizure medications, without requirement of local treatment or corticosteroids at randomization;7. LVEF (left ventricular ejection fraction) of at least 50% measured by echocardiogram(ECHO) or multiple-gated acquisition scan (MUGA); and8. Fasting glucose <126 mg / dL and HbAlc <6.4%.

[0150] Maintenance phase inclusion criteria:1. Completed 4-8 cycles of induction therapy;2. Achieved PR, CR, SD, non CR / non PR per RECIST vl.l after induction treatment;3. LVEF of >50% (by ECHO or MUGA); and4. Adequate hematologic, organ function, and serology tests at randomization.

[0151] Key exclusion criteria1. Prior treatment in the unresectable LA / mBC setting with any agent whose mechanism of action is to inhibit the PI3K / AKT / mTOR pathway;2. Systemic non-hormonal anticancer therapy for HER2+ unresectable LA / mBC prior to initiation of induction therapy;3. History of, or active, inflammatory bowel disease;4. Disease progression within 6 months of receiving HER2 -targeted therapy;5. Type 2 diabetes requiring ongoing systemic treatment at study entry or any history of Type 1 diabetes;6. Clinically significant and active liver disease, including severe liver impairment, viral or other hepatitis, current alcohol abuse, or cirrhosis;7. Symptomatic active lung disease, including pneumonitis or interstitial lung disease;8. History of leptomeningeal disease or carcinomatous meningitis;9. Serious infection requiring intravenous antibiotics within 7 days prior to Day 1 of Cycle1; and10. Active inflammatory or infectious eye conditions or eye conditions requiring medical or surgical intervention during study treatment.

[0152] Many modifications and other embodiments of the inventions set forth herein will come to mind to one skilled in the art to which these inventions pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the inventions are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

CLAIMSWe claim:

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 inavolisib and PH FDC SC, wherein said combination therapy is administered over a 21 -day cycle.

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. administering inavolisib QD on days 1-21 of a first 21 -day cycle; and b. administering PH FDC SC on day 1 of a first 21-day cycle.

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

4. The method of claim 3, wherein the induction therapy comprises administering PH 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. administering PH FDC SC on day 1 of each 21-day cycle; and b. administering paclitaxel on days 1, 8 and 15 of each 21-day cycle.

7. The method of any one of claims 1 to 6, further comprising one or more additional 21-day cycles comprising: a. administering inavolisib on days 1-21 of each additional 21-day cycle; and b. administering PH FDC SC on day 1 of each additional 21-day cycle.

8. The method of any one of claims 1 to 7, wherein inavolisib is administered at an amount of 9 mg.

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

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

11. The method of any one of claims 1 to 10, wherein the patient has left ventricular ejection fraction (LVEF) 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 comprising administering to the patient fulvestrant once about every four weeks at a dose of 500 mg by intramuscular (IM) infusion.

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

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

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 to the patient a combination therapy according to the methods of any one of claims 1 to 15.

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

18. A combination therapy comprising inavolisib and PH FDC SC for use in the treatment of a PIK3CA-mutated HER2 -positive breast cancer.

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

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