Combination therapies for use in the treatment of breast cancer

Abstract

Provided are combination therapies comprising inavolisib, a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib or abemaciclib), and letrozole; and methods of treating endocrine-sensitive PIK3CA-mutated, HR+ and HER2– advanced breast cancer in a patient comprising administering a therapeutically effective amount of inavolisib, a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib or abemaciclib), and letrozole.

Description

Docket No. P39790-WO-1COMBINATION THERAPIES FOR TREATMENT OF BREAST CANCERCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent ApplicationNo. 63 / 749,267, filed January 24, 2025, the contents of which are incorporated by reference herein in their entireties.FIELD OF THE INVENTION

[0002] The invention relates generally to treatment of PIK3CA-mutant cancer patients by administering a PI3K inhibitor, inavolisib, in combination with a CDK4 / 6 inhibitor and an endocrine therapy for the treatment of endocrine-sensitive breast cancers.BACKGROUND

[0003] Breast cancer is the most common cancer among women. Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC) accounts for 65%-70% of all breast cancers (Howlader et al. JNCI 2014, 106(5)). Current treatments for advanced or metastatic disease focus on prolonging life and improving or maintaining quality of life. Preventing resistance to therapy and ultimately achieving a cure remain unmet needs in this disease setting.

[0004] Study WO41554 (INAVO120) is a Phase III, randomized, double-blind, placebo-controlled, multicenter, global study designed to compare the efficacy, safety, and tolerability of the triplet combination of inavolisib plus palbociclib and fulvestrant versus placebo plus palbociclib and fulvestrant in patients with PIK3CA-mutated, HR-positive, HER2 -negative locally advanced or metastatic breast cancer whose disease progressed during treatment or within 12 months of completing adjuvant endocrine therapy and who have not received prior systemic therapy for locally advanced or metastatic disease. Study WO41554 study met its primary endpoint of progression free survival (PFS) and key secondary endpoints of overall survival (OS), demonstrating a statistically significant and clinically meaningful improvement compared to palbociclib and fulvestrant alone with manageable safety and good tolerability.SUMMARY OF THE INVENTION

[0005] The present disclosure provides a combination therapy comprising a PI3K inhibitor (e.g., inavolisib), a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and an endocrine therapy (e.g., fulvestrant or letrozole) for the treatment of endocrine-sensitive breast cancers.1#7024505Docket No. P39790-WO-1

[0006] One aspect of the present disclosure provides a combination therapy comprising a PI3K inhibitor (e.g., inavolisib), a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and letrozole for the treatment of breast cancers.

[0007] The disclosure further provides methods of treating endocrine-sensitive PIK3CA-mutated, hormone receptor positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) in a patient comprising administering a therapeutically effective amount of inavolisib, a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and an endocrine therapy (e.g., letrozole).

[0008] In one aspect, the present disclosure provides a method of treating an endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer in a patient, comprising administering a therapeutically effective amount of inavolisib, palbociclib and letrozole.

[0009] In one aspect, the present disclosure provides a method of treating an endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer in a patient, comprising administering a therapeutically effective amount of inavolisib, ribociclib and letrozole.

[0010] In one aspect, the present disclosure provides a method of treating an endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer in a patient, comprising administering a therapeutically effective amount of inavolisib, abemaciclib and letrozole.

[0011] Also provided is a combination for use in treating an endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer, wherein said combination comprises inavolisib, a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and an endocrine therapy (e.g., letrozole).

[0012] Also provided is a use of a combination in the manufacture of a medicament for treating an endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer, wherein said combination comprises inavolisib, a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and an endocrine therapy (e.g., letrozole).

[0013] In some embodiments, inavolisib is adminstered at a 9 mg daily dose.

[0014] In some embodiments, provided is a method of treating advanced breast cancer in a patient having endocrine-sensitive PIK3CA-mutated, hormone receptor positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer, the method comprising administering to the patient a combination therapy comprising inavolisib, palbociclib and letrozole, wherein said combination therapy is administered over a 28-day cycle.

[0015] In some embodiments, provided is a method of treating advanced breast cancer in a patient having endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer,Docket No. P39790-WO-1the method comprising administering to the patient a combination therapy comprising a dosing regimen comprising:a. administering inavolisib QD on days 1-28 of a 28-day cycle;b. administering palbociclib QD on days 1-21 of a 28-day cycle; andc. administering letrozole QD on days 1-28 of a 28-day cycle.

[0016] In some embodiments, provided is a method of treating advanced breast cancer in a patient having endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer, the method comprising administering to the patient a combination therapy comprising a dosing regimen comprising:a. administering inavolisib QD on days 1-28 of a first 28-day cycle;b. administering palbociclib QD on days 1-21 of a first 28-day cycle; andc. administering letrozole QD on days 1-28 of a first 28-day cycle.

[0017] In some of these embodiments, the method further comprises one or more additional 28-day cycles comprising:a. administering inavolisib on days 1-28 of each additional 28-day cycle;b. administering palbociclib on days 1-21 of each additional 28-day cycle; and c. administering letrozole on days 1-28 of each additional 28-day cycle.

[0018] Also provided is a combination for use in treating advanced breast cancer in a patient having endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer, wherein said combination comprises inavolisib, palbociclib and letrozole, and wherein said combination is administered over a 28-day cycle.

[0019] Also provided is a combination for use in treating an endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer, wherein said combination is administered in a combination therapy comprising a dosing regimen comprising:a. administering inavolisib QD on days 1-28 of a 28-day cycle;b. administering palbociclib QD on days 1-21 of a 28-day cycle; andc. administering letrozole QD on days 1-28 of a 28-day cycle.

[0020] Also provided is a use of a combination in the manufacture of a medicament for treating an endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer, wherein said combination comprises inavolisib, palbociclib and letrozole, and wherein said combination is administered over a 28-day cycle.

[0021] Also provided is a use of a combination in the manufacture of a medicament for treating an endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer, wherein said combination is administered in a combination therapy comprising a dosing regimen comprising:Docket No. P39790-WO-1a. administering inavolisib QD on days 1-28 of a 28-day cycle;b. administering palbociclib QD on days 1-21 of a 28-day cycle; andc. administering letrozole QD on days 1-28 of a 28-day cycle.

[0022] In some of these 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 administered at an amount of 9 mg, e.g., in an oral tablet. In some embodiments, palbociclib is administered at an amount of 125 mg, e.g., in an oral capsule or tablet. In some embodiments, letrozole is administered at an amount of 2.5 mg. e.g., in an oral tablet.

[0023] In a further aspect, provided is a method of inhibiting tumor growth or producing / increasing tumor regression in a patient having endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer, the method comprising administering to the patient a combination therapy according to the methods detailed herein.

[0024] In another aspect, provided is a combination for use in inhibiting tumor growth or producing / increasing tumor regression in a patient having endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer, according to the combination for use detailed herein.

[0025] 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 endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer, according to the combinations or uses detailed herein.

[0026] In some of these embodiments, the patient has ER-positive and / or progesterone receptorpositive tumor. In some embodiments, the patient has de-novo HR+, HER2- advanced breast cancer. In some embodiments, the patient has relapsed HR+, HER2- advanced breast cancer after at least 2 years of standard neoadj uvant / adjuvant endocrine therapy (e.g., tamoxifen, anastrozole, letrozole, exemestane, and / or oral selective estrogen receptor degrader) without disease progression during that treatment and disease-free interval of at least 1 year since the completion of that treatment. In some embodiments, the patient has bilateral breast cancers which are both HR-positive and HER2 -negative. In some embodiments, he patient has adequate hematologic and organ function within 14 days prior to initiation of study treatment. In some embodiments, the patient is post-menopausal (e.g., a post-menopausal women). In some embodiments, the patient is premenopausal or perimenopausal (e.g., a premenopausal or a perimenopausal women). In some embodiments, the patient is male.

[0027] Further provided is a method of preventing or delaying development of resistance of a tumor (e.g., breast cancer) to a therapy containing palbociclib, comprising administering aDocket No. P39790-WO-1combination therapy comprising inavolisib, palbociclib and letrozole. In some embodiments, the combination therapy is administered according to any methods as detailed herein.

[0028] 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 palbociclib, wherein said combination comprises inavolisib, palbociclib and letrozole. In some embodiments, said combination is administered according to any uses as detailed herein.

[0029] 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 palbociclib, wherein said combination comprises inavolisib, palbociclib and letrozole. In some embodiments, said combination is administered according to any uses as detailed herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0030] FIG 1 shows the trial schema of the INAVO123 phase 3 study designed to evaluate the efficacy and safety of the combination of inavolisib plus a cyclin-dependent kinase 4 and 6 inhibitor (CDK4 / 6i) (e.g., palbociclib) and letrozole versus placebo plus a CDK4 / 6 inhibitor (e.g., palbociclib) and letrozole in the first-line setting in patients with endocrine-sensitive PIK3CA-mutated, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), advanced breast cancer (ABC).The abbreviations are: ABC = advanced breast cancer; ctDNA = circulating-tumor DNA; ESMO = European Society for Medical Oncology; ET = endocrine therapy; FBG = fasting blood glucose; FoundationOne® Liquid CDx = FILCDx; FMI = Foundation Medicine, Inc; HbAlc = glycated hemoglobin; PD = progressive disease; PIK3CA = phosphatidylinositol 4, 5 -bisphosphate 3-kinase catalytic subunit alpha isoform; PO = by mouth; PRO = patient reported outcome; QD = once a day; RECIST = Response Evaluation Criteria in Solid Tumors.aUsing FILCDx at FMI or the alternative Sponsor-designated laboratory in regions where FMI is not available.bEndocrine-sensitivity for this study is derived from the ESMO definitions of primary or secondary endocrine resistance (Cardoso et al. Ann Oncol. 2020; 31:1623-49). Patients with ABC that meets either of the definitions of endocrine resistance will be excluded from participation.cIf no RECIST-PD by study treatment discontinuation.

[0031] FIG 2 shows the trial schema of the INAVO123 phase 3 study showing CDK4 / 6 inhibitors palbociclib, riboci clib or abemaciclib.See abbreviations for FIG 1; . BID = twice a day.aUsing FILCDx at FMI or the alternative Sponsor-designated laboratory in regions where FMI is not available.bEndocrine-sensitivity for this study is derived from the ESMO definitions ofDocket No. P39790-WO-1primary or secondary endocrine resistance (Cardoso et al. 2020). Participants with ABC that meets either of the definitions of endocrine resistance will be excluded from participation.cUp to 28 days of endocrine monotherapy prior to randomization is permitted.dIf no RECIST-PD by study treatment discontinuation.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0032] 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.

[0033] 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.

[0034] 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).Docket No. P39790-WO-1

[0035] “ Time to progression” or “TTP” refers to the time from randomization until objective tumor progression.

[0036] “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

[0037] “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

[0038] “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.

[0039] “ Clinical benefit rate” or “CBR” refers to the proportion of patients with stable disease for at least 24 weeks or with confirmed complete or partial response, as determined by the investigator according to RECIST vl.l.

[0040] “ Overall survival” or “OS” refers to the time from enrollment to death from any cause.

[0041] “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.

[0042] “Complete response” or “CR” refers to the disappearance of all target lesions and non-target lesions and (if applicable) normalization of tumor marker level.

[0043] “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.

[0044] “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.

[0045] “ 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.

[0046] 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.Docket No. P39790-WO-1

[0047] 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.

[0048] “QD” refers to administration of a compound once daily.

[0049] 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.

[0050] "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.

[0051] 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. 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 diseaseDocket No. P39790-WO-1and may guide treatment. Pharmacodynamic biomarkers confirm drug activity, and enables optimization of dose and administration schedule.

[0052] “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, 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.

[0053] A "chemotherapeutic agent" is a biological (large molecule) or chemical (small molecule) compound useful in the treatment of cancer, regardless of mechanism of action.

[0054] 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.

[0055] 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, -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.

[0056] 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, phosphoricDocket No. P39790-WO-1acid 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.

[0057] 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.

[0058] 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 a synergistic 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 parallelDocket No. P39790-WO-1as 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.Clinical CompoundsInavolisib:

[0059] Inavolisib is a potent and selective inhibitor of the Class I PI3K catalytic subunit alpha isoform protein (pl 10a; encoded by the PIK3CA gene), with > 300-fold less potent biochemical inhibition for other Class I PI3Ks, including the beta, delta, and gamma isoforms, and with increased potency in tumor cells bearing mutant pl 10a over cells bearing wild type (WT) pl 10a.

[0060] Inavolisib, ITOVEBI® Genentech, Inc., CAS Registry Number 2060571-02-8, US9650393; named as (5)-2-((2-((5)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[ / ]imidazo[l,2-J][l,4]oxazepin-9-yl)amino)propanamide, has the structure:

[0061] 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.

[0062] Inavolisib exerts its activity by binding to the ATP binding site of pl 10a, thereby inhibiting the phosphorylation of membrane-bound phosphatidylinositol 4, 5 -bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). Inhibiting the phosphorylation of PIP2 to PIP3 decreases downstream activation of pathway effectors including AKT and S6RP, resulting in decreased cellular proliferation, metabolism, and angiogenesis.Docket No. P39790-WO-1Palbociclib:

[0063] Palbociclib is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6 (Finn et al (2009) Breast cancer research : BCR 11 (5):R77; Rocca et al (2014) Expert Opin Pharmacother 15 (3):407-20; US 6936612; US 7863278; US 7208489; US 7456168).Palbociclib can be prepared and characterized as described in US 7345171. IBRANCE® is approved for the treatment of breast cancer.

[0064] Palbociclib (PD-0332991, IBRANCE®, Pfizer, Inc., CAS Reg. No. 571190-30-2), named as 6-acetyl-8-cyclopentyl-5-methyl-2-(5-(piperazin-l-yl)pyridin-2-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one, has the structure:

[0065] Palbociclib is a CDK4 / 6 inhibitor and, in combination with letrozole or fulvestrant, an effective treatment for postmenopausal patients with HR+ (positive) / HER2- (negative) breast cancer. In combination with letrozole or fulvestrant, the main toxicity of palbociclib is neutropenia (Finn et al (2015) Lancet Oncol 16:25-35; Turner et al (2015) N Engl J Med 373:209-19). In combination with letrozole, 36% of patients required > 1 dose reduction of palbociclib; dose holds and cycle delays were reported in 70% and 68% of patients, respectively (Finn et al (2016) J Clin Oncol 34(suppl; abstr 507)). In combination with fulvestrant, 34% of patients required > 1 dose reduction of palbociclib; dose holds and cycle delays were reported in 54% and 36% of patients, respectively (Cristofanilli et al. (2016) Lancet Oncol 17:425-39).

[0066] Other exemplary CDK4 / 6 inhibitors include, but are not limited to: ribociclib (Butanedioic acid — 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-l-yl) pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (1 / 1); marketed as KISQALI®); abemaciclib, (2-Pyrimidinamine, N-[5-[(4-ethyl-l-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4- fluoro-2-methyl-l-(l-methylethyl)-lH-benzimidazol-6-yl], marketed as VERZENIO®); and trilaciclib (2'-((5-(4-methylpiperazin-l-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro(cyclohexane-l,9'-pyrazino(r,2':l,5)pyrrolo(2,3-d)pyrimidin)-6'-one).Docket No. P39790-WO-1Ribociclib:

[0067] Ribociclib is a selective, small molecule inhibitor of the cyclin-dependent kinases CDK4 and CDK6 that blocks the phosphorylation of Rb protein, thereby preventing cell-cycle progression from G1 into S phase of the cell and inducing G1 phase arrest.

[0068] Ribociclib has chemical name 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-l-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide and has the structure:

[0069] Ribociclib is marketed as KISQALI®. KISQALI® is approved by the FDA in combination with an aromatase inhibitor for the adjuvant treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence, and for the treatment of adults with HR-positive, HER2-negative advanced or metastatic breast cancer in combination with: an aromatase inhibitor as initial endocrine-based therapy; or fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy. KISQALI® film-coated tablets are supplied for oral use and contain 200 mg of ribociclib free base (equivalent to 254.40 mg ribociclib succinate). A recommended 600 mg starting dose is taken orally in three 200 mg tablets.Abemaciclib:

[0070] Abemaciclib is a small molecule inhibitor of the cyclin-dependent kinases CDK4 and CDK6. Abemaciclib has chemical nameN-[5-[(4-Ethyl-l-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-l-(l -methylethyl)- lH-benzimidazol-6-yl]-2-pyrimidinamine, and has the structure:Abemaciclib is marketed as VERZENIO®. VERZENIO® is approved by the FDA as monotherapy and in combination with fulvestrant for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrineDocket No. P39790-WO-1therapy. Abemaciclib has been approved as a monotherapy in patients with HR+, HER2-negative advanced or metastatic breast cancer with disease progression following ET and prior chemotherapy in the metastatic setting.Letrozole:

[0071] 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.

[0072] 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:Combination Therapy

[0073] Provided herein are combinations or combination therapies comprising a PI3K inhibitor (e.g., inavolisib), a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and an endocrine therapy (e.g., fulvestrant or letrozole). In one aspect, provided is a combination or combination therapy comprising a PI3K alpha (PI3Ka) inhibitor (e.g., inavolisib), a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and an endocrine therapy (e.g., fulvestrant or letrozole). In one embodiment, the combination or combination therapy comprises inavolisib, palbociclib and letrozole. In one embodiment, the combination or combination therapy comprises inavolisib, ribociclib and letrozole. In one embodiment, the combination or combination therapy comprises inavolisib, abemaciclib and letrozole.

[0074] 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, a CDK4 / 6 inhititor (e.g., palbociclib, ribociclib, or abemaciclib) and letrozole. In oneDocket No. P39790-WO-1embodiment, the agents of the combination or combination therapy described herein are supplied in a kit in a form ready for administration or, for example, for reconstitution. 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.

[0075] 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.

[0076] 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 shelflife permit. One or more components of a kit may be sterile and / or may be contained within sterile packaging.Methods

[0077] Provided herein are methods of treating advanced breast cancer. In one embodiment, the method comprises treating advanced breast cancer in a patient having endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer, by administering to the patient a combination therapy that includes a PI3K inhibitor (preferably a PI3Ka inhibitor, e.g., inavolisib), a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and an endocrine therapy (e.g., fulvestrant or letrozole).

[0078] Also provided are methods of treating an endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer in a patient comprising administering a therapeutically effective amount of inavolisib, or a pharmaceutically acceptable salt thereof, a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), and an endocrine therapy (e.g., fulvestrant or letrozole). In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib or abemaciclib. In some embodiments, the endocrine therapy is a selective estrogen receptor down-regulator (e.g., fulvestrant). In some embodiments, the endocrine therapy is an aromatase inhibitor (e.g., a non-steroidal aromatase inhibitor such as letrozole).

[0079] In one aspect, provided is a method of treating an endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer in a patient comprising administering a therapeutically effective amount of inavolisib, palbociclib and letrozole.

[0080] In some embodiments, provided is a method of treating advanced breast cancer in a patient having endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer,Docket No. P39790-WO-1the method comprising administering to the patient a combination therapy comprising inavolisib, palbociclib and letrozole, wherein said combination therapy is administered over a 28-day cycle.[0081| In some embodiments, provided is a method of treating advanced breast cancer in a patient having endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer, the method comprising administering to the patient a combination therapy comprising a dosing regimen comprising:a. administering inavolisib QD on days 1-28 of a first 28-day cycle;b. administering palbociclib QD on days 1-21 of a first 28-day cycle; andc. administering letrozole QD on days 1-28 of a first 28-day cycle.

[0082] In some of these embodiments, the method further comprises one or more additional 28-day cycles comprising:a. administering inavolisib on days 1-28 of each additional 28-day cycle;b. administering palbociclib on days 1-21 of each additional 28-day cycle; and c. administering letrozole on days 1-28 of each additional 28-day cycle.

[0083] In one aspect, provided is a method of treating an endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer in a patient comprising administering a therapeutically effective amount of inavolisib, ribociclib and letrozole.

[0084] In some embodiments, provided is a method of treating advanced breast cancer in a patient having endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer, the method comprising administering to the patient a combination therapy comprising inavolisib, ribociclib and letrozole, wherein said combination therapy is administered over a 28-day cycle.

[0085] In some embodiments, provided is a method of treating advanced breast cancer in a patient having endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer, the method comprising administering to the patient a combination therapy comprising a dosing regimen comprising:a. administering inavolisib QD on days 1-28 of a 28-day cycle;b. administering ribociclib QD on days 1-21 of a 28-day cycle; andc. administering letrozole QD on days 1-28 of a 28-day cycle.

[0086] In one aspect, provided is a method of treating an endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer in a patient comprising administering a therapeutically effective amount of inavolisib, abemaciclib and letrozole.

[0087] In some embodiments, provided is a method of treating advanced breast cancer in a patient having endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer,Docket No. P39790-WO-1the method comprising administering to the patient a combination therapy comprising inavolisib, abemaciclib and letrozole, wherein said combination therapy is administered over a 28-day cycle.

[0088] In some embodiments, provided is a method of treating advanced breast cancer in a patient having endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer, the method comprising administering to the patient a combination therapy comprising a dosing regimen comprising:a. administering inavolisib QD on days 1-28 of a 28-day cycle;b. administering abemaciclib BID on days 1-28 of a 28-day cycle; andc. administering letrozole QD on days 1-28 of a 28-day cycle.

[0089] In some embodiments, the patient has endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer. 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, M1043I / 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 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, KI 11N / 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 E542K, E545K, Q546R, H1047L and H1047R. 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.

[0090] 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 ofDocket No. P39790-WO-1eligible 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 is performed using a Sponsor pre-approved PCR- or NGS-based assay at a CLIA-certified or equivalent laboratory.

[0091] In one embodiment, the method includes a combination therapy comprising (i) inavolisib; (ii) palbociclib; and (iii) letrozole. In one embodiment, the method includes a combination therapy comprising (i) inavolisib; (ii) palbociclib; and (iii) letrozole administered in accordance with a dosing regimen described herein.

[0092] In one embodiment, the method includes a combination therapy comprising (i) inavolisib; (ii) ribociclib; and (iii) letrozole. In one embodiment, the method includes a combination therapy comprising (i) inavolisib; (ii) ribociclib; and (iii) letrozole administered in accordance with a dosing regimen described herein.

[0093] In one embodiment, the method includes a combination therapy comprising (i) inavolisib; (ii) abemaciclib; and (iii) letrozole. In one embodiment, the method includes a combination therapy comprising (i) inavolisib; (ii) abemaciclib; and (iii) letrozole administered in accordance with a dosing regimen described herein.

[0094] In a further aspect, provided is a method of inhibiting tumor growth or producing / increasing tumor regression in a patient having endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer, the method comprising administering to the patient a combination therapy according to the methods detailed herein.

[0095] In some embodiments, estrogen receptor (ER)-positive and / or progesterone receptor-positive tumor are documented according to American Society of Clinical Oncology / College of American Pathologists (ASCO / CAP) guidelines, defined as > 1% of tumor cells stained positive based on the most recent tumor biopsy and assessed locally.

[0096] In some embodiments HER2-negative tumor are documented according to ASCO / CAP guidelines, defined as a HER2 immunohistochemistry (IHC) score of 0 or 1+, or an IHC score of 2+ accompanied by a negative fluorescence, chromogenic, or silver in situ hybridization test indicating the absence of HER2 gene amplification, or a HER2 / CEP17 ratio of < 2.0 based on the most recent tumor biopsy and assessed locally.

[0097] In some embodiments, the patient is women or men >18 years of age.

[0098] In some embodiments, the patient is postmenopausal (e.g., a postmenopausal female). Postmenopausal female is defined by at least one of the following criteria: (1) Age > 60 years; (2) Age < 60 years and 12 months of amenorrhea plus follicle-stimulating hormone and plasma estradiol levels within postmenopausal range by local laboratory assessment in the absence of oralDocket No. P39790-WO-1contraceptive pills, hormone replacement therapy, or gonadotropin releasing hormone agonist or antagonist; (3) Documented bilateral oophorectomy (> 14 days prior to first treatment on Day 1 of Cycle 1 and recovery to baseline).

[0099] In some embodiments, the patient is premenopausal or perimenopausal female (i.e., not meeting the criteria for postmenopausal) and has been treated with luteinizing hormone-releasing hormone (LHRH) agonist therapy (e.g., goserelin or leuprolide) beginning at least 2 weeks prior to Day 1 of Cycle 1 and continuing for the duration of study treatment.

[0100] In some embodiments, the patient is male and has been treated with with LHRH agonist therapy (e.g., goserelin or leuprolide) beginning at least 2 weeks prior to Day 1 of Cycle 1 and continuing for the duration of study treatment.

[0101] 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. In some embodiments, palbociclib, ribociclib, abemaciclib, fulvestrant or letrozole, where applicable, is administered at its approved dosage by an approved route of administration.

[0102] Agents in a combination therapy detailed herein may be administered simultaneously or sequentially. Two of the triplets of a combination therapy may be administer simultaneously while the third agent may be adminstered before or after. For example, in one embodiment of the methods described herein, administration of inavolisib occurs before administration of another agent (e.g. letrozole). In one embodiment of the methods described herein, administration of inavolisib occurs before administration of letrozole and the administration of letrozole occurs before the administration of a CDK4 / 6 inhibitor (e.g. palbociclib, ribociclib or abemaciclib). In another embodiment, inavolisib is administered prior to or concurrently with the CDK4 / 6 inhibitor (e.g. palbociclib, ribociclib or abemaciclib) and letrozole is administered thereafter.

[0103] 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.

[0104] In one embodiment of the methods described herein, palbociclib is administered as an agent of the triple combination therapy described herein. In one embodiment, palbociclib is administered orally at an amount of 125 mg, 100 mg, or 75 mg. In another embodiment, palbociclib is administered orally at an amount of 125 mg. In another embodiment, palbociclib is administered orally at an amount of 100 mg. In still another embodiment, palbociclib is administered orally at an amount of 75 mg. Is such embodiments, palbociclib is administered QDDocket No. P39790-WO-1on days 1-21 of each 28-day cycle. In another embodiment of the methods described herein, palbociclib is administered in accordance with a package insert. In one embodiment, palbociclib is administered orally QD on days 1-21 of each 28-day cycle at an amount described herein. In still another embodiment, the amount of palbociclib is modified (e.g. reduced) from the initial dosage. In one such embodiment, the amount of palbociclib administered is reduced from 125 mg to 100 mg and can be, in one embodiment, further reduced to 75 mg. In another embodiment, palbociclib is administered in a dosing regimen as described herein.

[0105] In some embodiments, palbociclib is administered at an amount of 125 mg, e.g., in an oral capsule or tablet.

[0106] In one embodiment of the methods described herein, ribociclib is administered as an agent of the triple combination therapy described herein. In one embodiment, ribociclib is administered orally at an amount of 200 mg, 400 mg, or 600 mg, e.g., in one, two, or three 200 mg oral tablets, respectively. In another embodiment, ribociclib is administered orally at an amount of 200 mg, e.g., in one 200 mg oral tablet. In another embodiment, ribociclib is administered orally at an amount of 400 mg, e.g., in two 200 mg oral tablets. In still another embodiment, ribociclib is administered orally at an amount of 600 mg, e.g., in three 200 mg oral tablets. In such embodiments, ribociclib is administered QD on days 1-21 of each 28-day cycle. In another embodiment of the methods described herein, ribociclib is administered in accordance with a package insert. In one embodiment, ribociclib is administered orally QD on days 1-21 of each 28-day cycle at an amount described herein. In still another embodiment, the amount of ribociclib is modified (e.g. reduced) from the initial dosage. In one such embodiment, the amount of ribociclib administered is reduced from 600 mg to 400 mg and can be, in one embodiment, further reduced to 200 mg. In another embodiment, the amount of ribociclib administered is reduced from 400 mg to 200 mg. In another embodiment, ribociclib is administered in a dosing regimen as described herein.

[0107] In one embodiment of the methods described herein, abemaciclib is administered as an agent of the triple combination therapy described herein. In one embodiment, abemaciclib is administered orally at an amount of 50 mg, 100 mg, or 150 mg. In some embodiments, abemaciclib is administered orally at an amount of 150 mg, e.g., in one or more oral tablets. In some embodiments, abemaciclib is administered at an amount of 100 mg, e.g., in an oral tablet. In some embodiments, abemaciclib is administered at an amount of 50 mg, e.g., in an oral tablet. In such embodiments, abemaciclib is administered BID on days 1-28 of each 28-day cycle. In another embodiment of the methods described herein, abemaciclib is administered in accordance with a package insert. In one embodiment, abemaciclib is administered orally BID on days 1-28Docket No. P39790-WO-1of each 28-day cycle at an amount described herein. In still another embodiment, the amount of abemaciclib is modified (e.g. reduced) from the initial dosage. In one such embodiment, the amount of abemaciclib administered is reduced from 150 mg to 100 mg and can be, in one embodiment, further reduced to 50 mg. In another embodiment, abemaciclib is administered in a dosing regimen as described herein.

[0108] In another embodiment of the methods described herein, letrozole is administered at a dose of about 2.5 mg. In one embodiment of the methods described herein, letrozole is administered in accordance with a package insert. In one such embodiment, letrozole is administered orally at a dose of about 2.5 mg QD.

[0109] In some embodiments, letrozole is administered at an amount of 2.5 mg. e.g., in an oral tablet.[OHO] In one embodiment, the methods described herein include a combination therapy described herein administered according to a dosing regimen comprising one 28-day cycle. In another embodiment, the methods described herein include a combination therapy described herein administered according to a dosing regimen comprising a first 28-day cycle followed by additional 28-day cycles. In another embodiment, the methods described herein include a combination therapy described herein administered according to a dosing regimen comprising a first 28-day cycle followed by 2-1028-day cycles. In still another embodiment, the methods described herein include a combination therapy described herein administered according to a dosing regimen comprising a first 28-day cycle followed by 2-828-day cycles. In one embodiment of the methods described herein, the dosing regimen comprises a first 28-day cycle followed by 2-36, 2-30, 2-24, 2-18, 2-12, 2-10, 2-8, 2-6, or 2-428-day cycles.

[0111] Further embodiments of the methods of treating endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer are provided herein.

[0112] In one embodiment, the efficacy of the combination is measured as a function of PFS. In one such embodiment, PFS of the patient is increased by 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or more months compared to non-treatment or SOC treatment. In one embodiment, PFS is measured for at least 64 months following the first dosage of the combination therapy described herein. In another embodiment, the efficacy is measured as a function of PFS in a biomarker positive patient set (e.g. a biomarker panel as described herein including PIK3CA) comparable to a biomarker negative patient set.

[0113] In one embodiment, treatment with a combination therapy according to the methods provided herein increases a patient’s OS by 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 or more months comparable to non-treatment or SOC treatment. In one embodiment, treatment with aDocket No. P39790-WO-1combination therapy according to the methods provided herein increases the patient’s amount of ORR. In another embodiment, efficacy of response is measured as a function of DOR comparable to non-treatment or SOC treatment. In still another embodiment, efficacy of response is measured as a function of CBR comparable to non-treatment or SOC treatment.

[0114] In another embodiment, the TTP is increased in a patient following treatment with a combination therapy according to the methods provided herein. In another embodiment, the PFS is increased in a patient following treatment with a combination therapy according to the methods provided herein. In one embodiment provided herein a patient is diagnosed having a CR following treatment with a combination therapy according to the methods provided herein. In one embodiment provided herein a patient is diagnosed having a PR following treatment with a combination therapy according to the methods provided herein. In one embodiment provided herein a patient is diagnosed having SD following treatment with a combination therapy according to the methods provided herein.

[0115] In some embodiments, the patient has de-novo HR+, HER2- advanced breast cancer. In some embodiments, the patient has relapsed HR+, HER2- advanced breast cancer after at least 2 years of standard neoadj uvant / adjuvant endocrine therapy (e.g., with an aromatase inhibitor) without disease progression during that treatment and disease-free interval of at least 1 year since the completion of that treatment. Non-limiting examples of aromatase inhibitors include anastrozole, letrozole and exemestane. In some embodiments, the patient has HR+, HER2-advanced breast cancer that is de-novo or relapsed after at least 2 years of standardneoadj uvant / adjuvant endocrine therapy. In some embodiments, the patient has PIK3CA-mutated, HR+, HER2- advanced breast cancer that is de-novo or relapsed after at least 2 years of standard neoadj uvant / adjuvant endocrine therapy. In some embodiments, the patient is a premenopausal or peri-menopausal patient and has HR+, HER2- advanced breast cancer with relapse while on tamoxifen, after at least 2 years on tamoxifen).

[0116] 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 CDK4 / 6 inhibitor such as palbociclib, ribociclib, or abemaciclib). 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 resistantDocket No. P39790-WO-1during treatment. In some embodiments of the methods described herein, the cancer is at early stage or at late stage.[01171 Co-administration of inavolisib with a CDK4 / 6 inhibitor (e.g. palbociclib, ribociclib, or abemaciclib) and an endocrine therapy (e.g., letrozole) may prevent or delay development of resistance of a tumor (e.g., breast cancer) to a CDK4 / 6 inhibitor (e.g. palbociclib, ribociclib, or abemaciclib) or a combination of a CDK4 / 6 inhibitor (e.g. palbociclib, ribociclib, or abemaciclib) and an endocrine therapy (e.g., letrozole). Thus provided is a method of preventing or delaying development of resistance of a tumor (e.g., breast cancer) to a therapy containing a CDK4 / 6 inhibitor (e.g. palbociclib, ribociclib, or abemaciclib), 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 palbociclib, comprising administering a combination therapy comprising inavolisib, palbociclib and letrozole. 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 ribociclib, comprising administering a combination therapy comprising inavolisib, ribociclib and letrozole. 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 abemaciclib, comprising administering a combination therapy comprising inavolisib, abemaciclib and letrozole. In some embodiments, the combination therapy is administered according to any methods as detailed herein.

[0118] Also provided herein are methods of inhibiting tumor growth or producing tumor regression in a patient described herein by administering a combination therapy described herein.[0H9] In one embodiment provided herein is a method of producing or improving tumor regression in a patient described herein by administering a combination therapy described herein.

[0120] In one embodiment of the methods provided herein, inavolisib and letrozole are each administered QD in each 28-day cycle and palbociclib is administered QD on days 1-21 of each 28-day cycle.

[0121] In one embodiment of the methods provided herein, inavolisib and letrozole are each administered QD in each 28-day cycle and ribociclib is administered QD on days 1-21 of each 28-day cycle.

[0122] In one embodiment of the methods provided herein, inavolisib and letrozole are each administered QD in each 28-day cycle and abemaciclib is administered BID on days 1-28 of each 28-day cycle.

[0123] In some embodiments, the patient has adequate hematologic and organ function within 14 days prior to initiation of study treatment.Docket No. P39790-WO-1Biomarkers

[0124] 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.

[0125] 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 / AKTl / 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).

[0126] 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. 2011). 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 be collected 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, a CDK4 / 6 inhibitor (e.g. palbociclib, ribociclib, or abemaciclib), and fulvestrant or letrozole.Docket No. P39790-WO-1EXAMPLESAbbreviations:AEs, adverse events;CDK4 / 6i, cyclin-dependent kinase 4 / 6 inhibitor;CI, confidence interval;CR, complete response;ctDNA: circulating tumor DNA;D, day;ECOG, Eastern Cooperative Oncology Group;EORTC QLQ-C30: European Organisation for Research and Treatment of Cancer Quality of Life - Core 30 Questionnaire;FACT-G: Functional Assessment of Cancer Therapy-General questionnaireHbAlc, glycated haemoglobin;HER2, human epidermal growth factor receptor 2;NCLCTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; PrD, progressive disease;PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha;PR, partial response;PRO-CTCAE: Patient Reported Outcomes Common Terminology Criteria for Adverse Events; RECIST, Response Evaluation Criteria in Solid Tumors;SD, stable disease;TTCD: time to confirmed deterioration.Example 1 Phase 3 Clinical Study with Inavolisib / Palbociclib / Letrozole Combination

[0127] A Phase III, multicenter, randomized, double-blind, placebo-controlled study (INAVO123) is designed to evaluate the efficacy and safety of the combination of inavolisib plus a cyclin-dependent kinase 4 and 6 inhibitor (CDK4 / 6i) (e.g., palbociclib) and letrozole versus placebo plus a CDK4 / 6 inhibitor (e.g., palbociclib) and letrozole in the first-line setting in patients with endocrine-sensitive PIK3CA -mutated, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), advanced breast cancer (ABC). The trial design schema where the CDK4 / 6 inhibitor used is palbociclib is shown in FIG. 1. The study may be expanded to include other CDK4 / 6 inhibitor choices (e.g., ribociclib or abemaciclib). The design schema including CDK4 / 6 inhibitors palbociclib, ribociclib or abemaciclib are shown in FIG. 2.Docket No. P39790-WO-1Arms and Interventions

[0128] Experimental Arm: inavolisib + letrozole + CDK4 / 6i (palbociclib or ribociclib or abemaciclib).

[0129] Participants receive: (a) oral inavolisib once daily (QD); (b) oral palbociclib or ribociclib on Days 1-21 or oral abemaciclib BID on days 1-28 of each 28-day cycle; and (c) oral letrozole QD.

[0130] Placebo Comparator Arm: Placebo + letrozole + CDK4 / 6i (palbociclib or ribociclib or abemaciclib)

[0131] Participants receive: (a) oral placebo QD; (b) oral palbociclib or ribociclib on Days 1-21 or oral abemaciclib BID on days 1-28 of each 28-day cycle; and (c) oral letrozole QD.Outcome MeasuresTo evaluate efficacy:Primary Outcome Measure.

[0132] 1. Progression-Free Survival (PFS)[Time Frame: From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to 7 years)]Secondary Outcome Measure '.

[0133] 2. Overall Survival (OS)[Time Frame: From randomization to death from any cause (up to 7 years)]

[0134] 3. Investigator-assessed Objective Response Rate (ORR), defined as the proportion of participants with a CR and / or PR on at least two consecutive occasions >= 4 weeks apart, as determined by the investigator according to RECIST vl.l.[Time Frame: Up to 7 years]

[0135] 4. Investigator-assessed Duration of Response (DOR)[Time Frame: From the first occurrence of a confirmed objective response to the first occurrence of disease progression or death from any cause, whichever occurs first (up to 7 years)]

[0136] 5. Investigator-assessed Clinical Benefit Rate (CBR), defined as the proportion of participants with a CR, PR, and / or SD for at least 24 weeks, as determined by the investigator according to RECIST vl.l[Time Frame: Up to 7 years]To evaluate evaluate patient-reported pain severity, functioning, and HRQoL:

[0137] 6. Time to Confirmed Deterioration (TTCD) in Pain, defined as the time from randomization to the first documentation of a >= 2-point increase from baseline held for twoDocket No. P39790-WO-1consecutive timepoints on the "worst pain" item from the Brief Pain Inventory - Short Form (BPI-SF)[Time Frame: From baseline until end of follow-up (up to 7 years)]

[0138] 7. TTCD in Physical Function, defined as the time from randomization to the first documentation of a >= 10-point decrease from baseline held for two consecutive timepoints on the EORTC QLQ-C30 Physical Function scale (items 1-5)[Time Frame: From baseline until end of follow-up (up to 7 years)]

[0139] 8. TTCD in Role Function, defined as the time from randomization to the first documentation of a >= 10-point decrease from baseline held for two consecutive timepoints on the EORTC QLQ-C30 Role Function scale (items 6 and 7)[Time Frame: From baseline until end of follow-up (up to 7 years)]

[0140] 9. TTCD in Global Health Status, or TTCD in HRQoL, defined as the time from randomization to the first documentation of a >= 10-point decrease from baseline held for two consecutive timepoints on the EORTC QLQ-30 GHS / QoL scale (items 29 and 30)[Time Frame: From baseline until end of follow-up (up to 7 years)]To evaluate safety:

[0141] 10. Percentage of Participants with Adverse Events, or Incidence and severity of adverse events, with severity determined according to the NCI CTCAE v5.0[Time Frame: From baseline until end of follow-up (up to 7 years)]To evaluate tolerability:

[0142] 11. Number of Participants reporting Presence, Frequency, Severity, and / or Degree of Interference with Daily Function of Symptomatic Treatment Toxicities (diarrhea, nausea, vomiting, decreased appetite, fatigue, mouth sores, rash, muscle pain, joint pain, hot flashes and vaginal dryness), as assessed by NCI Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE)[Time Frame: Up to 7 years]

[0143] 12. Number of Participants reporting Each Response Option for Treatment Side-effect Bother Single-item General Population, Question 5 (GP5) from the Functional Assessment of Cancer Therapy-General Questionnaire; (FACT-G)[Time Frame: Up to 7 years]

[0144] 13. Change from Baseline in Symptomatic Treatment Toxicities as Assessed Through use of the PRO-CTCAE[Time Frame: Baseline up to 7 years]Docket No. P39790-WO-1

[0145] 14. Change from Baseline in Treatment Side-effect Bother as Assessed Through use of the FACT-G GP5 Item[Time Frame: Baseline up to 7 years]Eligibility

[0146] Minimum age: 18 years; all sex (not gender based) are accepted. Healthy volunteers are not accepted. The target population inclusion and exclusion criteria are as follows.[01471 Key Inclusion Criteria• Women or men with histologically or cytologically confirmed carcinoma of the breast that is locally advanced and / or metastatic and is not amenable to surgical or radiation therapy with curative intent• Documented ER-positive and / or progesterone receptor-positive tumor according to American Society of Clinical Oncology / College of American Pathologists (ASCO / CAP) guidelines, defined as > 1% of tumor cells stained positive based on the most recent tumor biopsy and assessed locally (Allison et al. J Clin Oncol 2020; 38:1346-66)• Documented HER2-negative tumor according to ASCO / CAP guidelines, defined as a HER2 immunohistochemistry (IHC) score of 0 or 1+ , or an IHC score of 2+ accompanied by a negative fluorescence, chromogenic, or silver in situ hybridization test indicating the absence of ERBB2 gene amplification, or a HER2 / CEP17 ratio of <2.0 based on the most recent tumor biopsy (or archived tumor sample if HER2 status was not retested on the most recent tumor biopsy) and assessed locally (Wolff et al. J Clin Oncol 2023; 41:3867-72)• De-novo HR+ , HER2- ABC, or, alternatively, relapsed HR+, HER2- ABC after at least 2 years of standard neoadj uvant / adjuvant endocrine therapy (e.g., tamoxifen, anastrozole, letrozole, exemestane, and / or oral selective estrogen receptor degrader) without disease progression during that treatment and disease-free interval of at least 1 year since the completion of that treatment (optional exception: pre- / peri-menopausal participants with relapse while on tamoxifen, after at least 2 years on tamoxifen)• Participants who have bilateral breast cancers which are both HR-positive and HER2-negative• Confirmation of biomarker eligibility• Qualifying PIK3CA mutation (determined by central ctDNA or pre-existing local tissue or ctDNA test)• Consent to provide fresh or archival tumor tissue specimen• Measurable disease per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v 1.1)Docket No. P39790-WO-1• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1• Adequate hematologic and organ function within 14 days prior to initiation of study treatment• Fasting blood glucose (FBG) <126 mg / dL and HbAic <6.5%

[0148] Exclusion Criteria• Pregnant or breastfeeding, or intention of becoming pregnant during the study or within the time frame in which contraception is required• Metaplastic breast cancer• Any prior systemic therapy for locally advanced unresectable or metastatic breast cancer (in some cases, up to 1 cycle of endocrine monotherapy is allowed)• Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any history of Type 1 diabetes• Any history of leptomeningeal disease or carcinomatous meningitis• Known and untreated, or active CNS metastases. Participants with a history of treated CNS metastases are eligible• Active inflammatory or infectious conditions in either eye or history of idiopathic or autoimmune-associated uveitis in either eye• Symptomatic active lung disease• History of or active inflammatory bowel disease• Any active bowel inflammation• Prior hematopoietic stem cell or bone marrow transplantation• Treatment with strong cytochrome P450 (CYP) 3 A4 inhibitors or strong CYP3 A4 inducers within 4 weeks or 5 drug-elimination half-lives, prior to initiation of study treatment

[0149] 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

Docket No. P39790-WO-1CLAIMSWe claim:

1. A method of treating advanced breast cancer in a patient having endocrine-sensitive PIK3CA-mutated, hormone receptor positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer, the method comprising administering to the patient a combination therapy comprising:(i) inavolisib;(ii) a CDK4 / 6 inhibitor; and(iii) letrozole,wherein said combination therapy is administered over a 28-day cycle.

2. The method of claim 1, wherein the CDK4 / 6 inhibitor is selected from palbociclib, riboci clib and abemaciclib.

3. The method of claim 1, wherein the CDK4 / 6 inhibitor is ribociclib.

4. The method of claim 1, wherein the CDK4 / 6 inhibitor is abemaciclib.

5. A method of treating advanced breast cancer in a patient having endocrine-sensitive PIK3CA-mutated, hormone receptor positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer, the method comprising administering to the patient a combination therapy comprising:(i) inavolisib;(ii) palbociclib; and(iii) letrozole,wherein said combination therapy is administered over a 28-day cycle.

6. A method of treating advanced breast cancer in a patient having endocrine-sensitive PIK3CA-mutated, HR+ and HER2- advanced breast cancer, the method comprising administering to the patient a combination therapy comprising a dosing regimen comprising:a. administering inavolisib QD on days 1-28 of a first 28-day cycle;b. administering palbociclib QD on days 1-21 of a first 28-day cycle; and c. administering letrozole QD on days 1-28 of a first 28-day cycle.

7. The method of claim 5 or 6, further comprising one or more additional 28-day cycles comprising:Docket No. P39790-WO-1a. administering inavolisib on days 1-28 of each additional 28-day cycle;b. administering palbociclib on days 1-21 of each additional 28-day cycle; and c. administering letrozole on days 1-28 of each additional 28-day cycle.

8. The method of any one of claims 1-7, wherein inavolisib is administered at an amount of 3, 6 or 9 mg.

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

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

11. The method of any one of claims 5-10, wherein palbociclib is administered at an amount of 125 mg in an oral capsule or tablet.

12. The method of any one of claims 1-11, wherein letrozole is administered at an amount of 2.5 mg in an oral tablet.

13. The method of any one of claims 1-12, wherein the patient has ER-positive and / or progesterone receptor-positive tumor.

14. The method of any one of claims 1-13, wherein the patient has de-novo HR+, HER2- advanced breast cancer.

15. The method of any one of claims 1-14, wherein the patient has relapsed HR+, HER2- advanced breast cancer after at least 2 years of standard neoadj uvant / adjuvant endocrine therapy without disease progression during that treatment and disease-free interval of at least 1 year since the completion of that treatment.

16. The method of any one of claims 1-15, wherein the patient has bilateral breast cancers which are both HR-positive and HER2-negative.

17. The method of any one of claims 1-16, wherein the patient has adequate hematologic and organ function within 14 days prior to initiation of treatment.

18. The method of any one of claims 1-17, wherein the patient is post-menopausal.

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