Methods of treating lung cancer

Abstract

Provided herein are methods and kits for use in treatment of lung cancer. In particular, the present disclosure provides methods and kits for treatment of lung cancer in a subject by administering osimertinib either in combination with or in sequentially following alisertib.

Description

Client Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 METHODS OF TREATING LUNG CANCER CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to United States Provisional Application Number 63 / 650,041, filed on May 21, 2024, the contents of which are hereby incorporated by reference in their entirety. FIELD

[0002] Provided herein are methods and kits for use in treatment of lung cancer. In particular, the present disclosure provides methods and kits for treatment lung cancer in a subject by administering osimertinib either in combination with or in sequentialy folowing alisertib. BACKGROUND

[0003] EGFR (epidermal growth factor receptor) serves as a critical regulator of celular growth and division, playing a fundamental role in various physiological processes. However, when alterations occur in the gene encoding EGFR this leads to gene mutations that can cause activation of aberant signaling pathways, uncontroled cel proliferation, and contribute to the onset of cancer. This phenomenon is particularly significant in the context of lung cancer, where EGFR mutations represent a prominent molecular subtype.

[0004] EGFR-positive lung cancer accounts for approximately 10–15% of al lung cancer cases in the United States, making it one of the most prevalent genetic mutations observed in this disease. This mutation predominantly manifests within the adenocarcinoma subtype of non-smal cel lung cancer (NSCLC), a form of lung cancer characterized by its resistance to traditional chemotherapy and distinctive histological features. Interestingly, patients diagnosed with EGFR- mutant lung cancer often exhibit minimal to no history of tobacco smoking, highlighting a unique epidemiological profile associated with this molecular subtype.

[0005] Curent treatment options for EGFR-positive lung cancer encompass a spectrum of therapeutic modalities, ranging from targeted therapies to traditional cytotoxic agents and surgical interventions. For example, EGFR Tyrosine Kinase Inhibitors (TKIs) occupy a central role in targeted therapy, exerting their efects by specificaly antagonizing the aberrant EGFR signaling cascade. Complementary approaches such as chemotherapy, immunotherapy, surgeryClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 for localized disease, and radiation therapy further expand into the variation of therapeutic treatments one could use to treat EGFR lung cancer, ofering multifaceted strategies for disease management.

[0006] Nevertheless, despite the aray of available treatments, formidable chalenges persist in the efective management of EGFR-mutant lung cancer. Foremost amongst these chalenges is the emergence of drug resistance, which undermines the eficacy of targeted therapies and treatments necessitating the exploration of novel therapeutic avenues. In particular, drug resistance in EGFR lung cancer occurs when the cancer cels become resistant to the efects of anticancer drugs, leading to treatment failure. This resistance can occur from the beginning of treatment (primary resistance) or develop over time, even after an initial response to therapy (acquired resistance), and involves various mechanisms like genetic mutations, activation of alternative signaling pathways, and changes in the tumor microenvironment. Moreover, the downstream efects of drug resistance not only have an implicit burden on the individual’s life and cancer prognosis but, also causes an undue economic burden associated with the further exploration and cost of EGFR-targeted therapies.

[0007] In addressing these chalenges, the need lies in the development of innovative therapeutic approaches that not only target EGFR mutations but also overcome issues related to drug resistance and treatment accessibility. SUMMARY

[0008] In one embodiment, provided herein are methods of treating lung cancer in a subject in need of treatment thereof. In some embodiments, the method comprises administering to the subject on a 28-day dose schedule, a daily dose of osimertinib in combination with a twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof, wherein:

[0009] the administered daily dose of osimertinib is from about 20 mg to about 240 mg and is administered on days 1-28 of the 28-day schedule; and

[0010] the administered twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is from about 20 mg to about 50 mg and is administered on days 1-3, 8-10, and 15-17 of the 28-day schedule. In some embodiments, the administered twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is from about 20 mg to about 50 mg and is administered on days 1-3, 8-11, and 15-17 of the 28-day schedule.Client Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101

[0011] In some embodiments in the above method, the administration of alisertib is simultaneous with the administration of osimertinib.

[0012] In other embodiments of the above method, the administration of alisertib is successive with the administration of osimertinib.

[0013] In stil yet other embodiments of the above method, the daily dose of osimertinib is from about 20 mg to about 100 mg.

[0014] In stil yet other embodiments of the above method, the daily dose of osimertinib is from about 40 mg to about 80 mg.

[0015] In stil yet other embodiments of the above method, the daily dose of osimertinib is about 80 mg.

[0016] In stil yet further embodiments of the above method, the twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is from about 30 mg to about 40 mg.

[0017] In stil yet further embodiments of the above method, the twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is about 20 mg.

[0018] In stil yet further embodiments of the above method, the twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is about 30 mg.

[0019] In stil yet further embodiments of the above method, the twice-daily dose of alisertib or pharmaceuticaly acceptable salt thereof is about 40 mg.

[0020] In stil yet further embodiments of the above method, the twice-daily dose of alisertib or pharmaceuticaly acceptable salt thereof is about 50 mg.

[0021] In stil yet further embodiments of the above method, the lung cancer is epidermal growth factor receptor (EGFR) mutated lung cancer.

[0022] In another embodiment, the present disclosure relates to a method of treating lung cancer in a subject in need of treatment thereof. In some embodiments, the method comprises administering to the subject on a 28-day dose schedule, a daily dose of osimertinib in combination with a twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof, wherein:

[0023] the administered daily dose of osimertinib is from about 20 mg to about 240 mg and is administered on days 1-28 of the 28-day schedule;Client Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101

[0024] the administered twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is from about 20 mg to about 50 mg and is administered on days 1-3, 8-10, and 15-17 of the 28-day schedule; and

[0025] the subject is determined not to contain one or more mutations in a p53 gene. In some embodiments, the administered twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is from about 20 mg to about 50 mg and is administered on days 1-3, 8- 11, and 15-17 of the 28-day schedule.

[0026] In some embodiments in the above method, the administration of alisertib is simultaneous with the administration of osimertinib.

[0027] In other embodiments of the above method, the administration of alisertib is successive with the administration of osimertinib.

[0028] In stil yet other embodiments of the above method, the daily dose of osimertinib is from about 20 mg to about 100 mg.

[0029] In stil yet other embodiments of the above method, the daily dose of osimertinib is from about 40 mg to about 80 mg.

[0030] In stil yet other embodiments of the above method, the daily dose of osimertinib is about 80 mg.

[0031] In stil yet further embodiments of the above method, the twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is from about 30 mg to about 40 mg.

[0032] In stil yet further embodiments of the above method, the twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is about 20 mg.

[0033] In stil yet further embodiments of the above method, the twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is about 30 mg.

[0034] In stil yet further embodiments of the above method, the twice-daily dose of alisertib or pharmaceuticaly acceptable salt thereof is about 40 mg.

[0035] In stil yet further embodiments of the above method, the twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is about 50 mg.

[0036] In stil yet further embodiments of the above method, the lung cancer is epidermal growth factor receptor (EGFR) mutated lung cancer.

[0037] In stil yet further embodiments of the above method, the one or more mutations in the p53 gene or lack thereof is determined by a sequencing assay.Client Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101

[0038] In yet a further embodiment, the present disclosure relates to methods of treating lung cancer in a subject. In some embodiments, the method comprises the steps of: treating lung cancer in a subject in need thereof, comprising:

[0039] a) determining if a sample obtained from the subject contains one or more mutations in a p53 gene;

[0040] b) selecting a subject having no mutations in the p53 gene based on the determination in step a); and

[0041] c) administering to the subject selected in step b), a daily dose of osimertinib in combination with a twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof, wherein:

[0042] the osimertinib and alisertib are administered on a 28-day schedule,

[0043] the administered daily dose of osimertinib is from about 20 mg to about 240 mg and is administered on days 1-28 of the 28-day schedule; and

[0044] the administered twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is from about 20 mg to about 50 mg and is administered on days 1-3, 8-10, and 15-17 of the 28-day schedule. In certain embodiments, the administered twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is from about 20 mg to about 50 mg and is administered on days 1-3, 8-11, and 15-17 of the 28-day schedule.

[0045] In some embodiments in the above method, the administration of alisertib is simultaneous with the administration of osimertinib.

[0046] In other embodiments of the above method, the administration of alisertib is successive with the administration of osimertinib.

[0047] In stil yet other embodiments of the above method, the daily dose of osimertinib is from about 20 mg to about 100 mg.

[0048] In stil yet other embodiments of the above method, the daily dose of osimertinib is from about 40 mg to about 80 mg.

[0049] In stil yet other embodiments of the above method, the daily dose of osimertinib is about 80 mg.

[0050] In stil yet further embodiments of the above method, the twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is from about 30 mg to about 40 mg.Client Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101

[0051] In stil yet further embodiments of the above method, the twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is about 20 mg.

[0052] In stil yet further embodiments of the above method, the twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is about 30 mg.

[0053] In stil yet further embodiments of the above method, the twice-daily dose of alisertib or pharmaceuticaly acceptable salt thereof is about 40 mg.

[0054] In stil yet further embodiments of the above method, the twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is about 50 mg.

[0055] In stil yet further embodiments of the above method, the lung cancer is epidermal growth factor receptor (EGFR) mutated lung cancer.

[0056] In stil yet further embodiments of the above method, the one or more mutations in the p53 gene or lack thereof is determined by a sequencing assay. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) wil be provided by the Ofice upon request and payment of the necessary fee.

[0058] Having thus described the presently disclosed subject mater in general terms, reference wil now be made to the accompanying Figures, which are not necessarily drawn to scale, and wherein:

[0059] FIG.1: A bar graph indicting radiographic response between 30 mg and 40mg of alisertib in diferent variations of mutations found in the EGFR (epidermal growth factor receptor) gene as described in the Examples.

[0060] FIG.2: A bar graph indicating the percentage of radiographic response in Econ 19del, L858R and L861Q to evaluate the efficacy of osimertinib and alisertib in osimertinib resistant patients as described in the Examples.

[0061] FIG.3: A Kaplan Meier line graph indicating the probability of progression free survival of patients treated with alisertib in combination with osimertinib over a maximum period of 30 months as described in the Examples.95% confidence intervals (CI) are indicated by the dashed lines.

[0062] FIG.4: A Kaplan Meier line graph indicating (A) the probability of progression free survival of a subject taking one or two or more lines of prior therapy and (B) the probability ofClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 progression free survival of a subject taking one or two or more prior tyrosine kinase inhibitors (TKIs) in a period of 30 months as described in the Examples.

[0063] FIG.5: A line graph indicating the probability of survival in a subject with two or more lines of prior therapy with no prior chemotherapy or prior chemotherapy in a period of 30 months as described in the Examples.

[0064] FIG.6: (A) A bar graph indicating the percent of radiographic response in TP53 mutations (TP53MUT) and TP53 wild-type (TP53WT) and (B) Response Evaluation Criteria in Solid Tumors (RECIST 1.1) in TP53MUT and TB53WT as described in the Examples.

[0065] FIG.7: A line graph indicating the probability of survival in TP53MUT and TB53WT subjects in a period of 30 months as described in the Examples. DETAILED DESCRIPTION DEFINITIONS

[0066] The terms "comprise(s)," "include(s)," "having," "has," "can," "contain(s)," and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms "a," "and", and "the" include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments "comprising," "consisting of," and "consisting essentialy of," the embodiments or elements presented herein, whether explicitly set forth or not.

[0067] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 69, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated. Unless otherwise defined herein, scientific, and technical terms used in connection with the present disclosure shal have the meanings that are commonly understood by those of ordinary skil in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shal include pluralities and plural terms shal include the singular.

[0068] The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies thatClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 10%.

[0069] In instances where a range of values is provided, it is understood that every value within that range, to the nearest tenth of the unit of the lower limit unless otherwise indicated by the context, including any other stated or intervening values within that range, fals within the scope of the present disclosure. Both the upper and lower limits of these smaler ranges may be included independently within the smaler ranges and are also considered part of the present disclosure, except where explicitly excluded by stated limits within the range. If the stated range includes one or both of its limits, ranges excluding either or both of these included limits are also considered part of the present disclosure.

[0070] As used herein, the term “alisertib” or “MLN8237”, as used interchangeably herein, refers to the selective Aurora A kinase inhibitor known as 4-{[9-chloro-7-(2-fluoro-6- methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid or pharmaceuticaly acceptable salts thereof. In one embodiment, the pharmaceuticaly acceptable salt is a sodium salt of alisertib also refered as to sodium 4-{[9-Chloro-7-(2-fluoro-6- methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate. Alisertib or a pharmaceuticaly acceptable salt thereof and their methods of preparation are described in U.S. Patent No.8,026,246; U.S. Patent No.9,765,076; and US Patent No.10,836,766, each of which is herein incorporated by reference in their entirety. Formulations of alisertib are disclosed in U.S. Patent No.9,173,846; U.S. Patent No.9,655,856; U.S. Patent No.10,888,523; U.S. Patent No.9,127,011; U.S. Patent No.9,504,693, the entirety of each of which is incorporated herein by reference. In one embodiment, provided herein is sodium 4-{[9-chloro-7- (2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate monohydrate. In another embodiment, provided herein is sodium 4-{[9-chloro-7-(2-fluoro-6- methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate polymorph Form 2, as described in U.S. Patent No.8,026,246, and US Patent No.8,653,064, each of which is hereby incorporated by reference in their entirety.

[0071] Throughout this application and unless specified otherwise, the terms 4-{[9-chloro-7- (2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid; 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-Client Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 yl]amino}-2-methoxybenzoic acid or a pharmaceuticaly acceptable salt thereof; sodium 4-{[9- chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2- methoxybenzoate; sodium 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4- d][2]benzazepin-2-yl]amino}-2-methoxybenzoate monohydrate; and sodium 4-{[9-chloro-7-(2- fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate polymorph Form 2, colectively are refered to herein as “alisertib.”

[0072] As used herein, the term “Aurora A kinase' refers to a serine / threonine kinases involved in regulating various aspects of cel division, particularly in the process of mitosis. Aurora A kinase is also known as AIK, ARK1, AURA, BTAK, STK6, STK7, STK15, AURORA2, MGC34538, and AURKA. A variety of celular proteins that play a role in cel division are substrates for phosphorylation by the Aurora A kinase enzyme, including, without limitation, p53, TPX-2, XIEg5 (in Xenopus), and D-TACC (in Drosophila). The Aurora A kinase enzyme is also itself a substrate for auto phosphorylation, e.g., at Thr288. In some embodiments, the Aurora A kinase is a human Aurora A kinase.

[0073] The term “inhibitor of Aurora A kinase” or “Aurora A kinase inhibitor” is used to signify a compound capable of interacting with Aurora A kinase and inhibiting its enzymatic activity. Inhibiting Aurora A kinase enzymatic activity means reducing the ability of Aurora A kinase to phosphorylate a Substrate peptide or protein. In various embodiments, such reduction of Aurora A kinase activity is at least about 65%, is at least about 70%, is at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99%. In various embodiments, the concentration of Aurora A kinase inhibitor required to reduce an Aurora A kinase enzymatic activity is less than about 1 μM, less than about 500 μM, less than about 100 mM, or less than about 50 mM.

[0074] Inhibition of Aurora A and inhibition of Aurora B result in markedly diferent celular phenotypes. (Proc. Natl. Acad. Sci. (2007) 104: 4106; Mol Cancer Ther, (2009) 8(7), 2046-56; Chem Biol. (2008) 15(6) 552-62). For example, inhibition of Aurora A in the absence of Aurora B inhibition results in increased mitotic index as measured by quantifying phosphorylated histone H3 on serine 10 (pHisH3). pHisH3 is a unique substrate of Aurora B in physiological systems (e.g. intact cels). In contrast, inhibition of Aurora B or dual inhibition of Aurora A and Aurora B results in a decrease in pHisH3. Accordingly, as used herein, the phrase “selective inhibitor of Aurora A kinase” or “selective Aurora A kinase inhibitor” refers to an inhibitor thatClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 exhibits an Aurora A kinase inhibitor phenotype at efective antitumor concentrations. In some embodiments, the selective Aurora A kinase inhibitor causes a transient mitotic delay, as measured by quantification of pHisH3, when administered to mice at a dose where the free fraction adjusted concentration (Cave) in plasma is equivalent to the free fraction adjusted concentration achieved in plasma in humans at the maximum tolerated dose (MTD). An example of a selective Aurora A kinase inhibitor is alisertib.

[0075] As used herein, the terms “cel proliferative disorder” or “cancer”, as used interchangeably herein, refer to a celular disorder characterized by uncontroled or dysregulated cel proliferation, decreased celular differentiation, inappropriate ability to invade surounding tissue, and / or ability to establish new growth at ectopic sites. “Cel proliferative disorder” or “cancer” include, but are not limited to, solid tumors and bloodborne tumors. The terms “cel proliferative disorder” and “cancer” encompass diseases of skin, tissues, organs, bone, cartilage, blood, and vessels. The terms “cel proliferative disorder” or “cancer” further encompass primary and metastatic cancers. As used herein, “cel proliferative disorders” include, but is not limited to, cancerous hyperproliferative disorders (e.g., brain, lung, squamous cel, bladder, gastric, pancreatic, breast, head, neck, renal, liver, kidney, ovarian, prostate, colorectal, colon, epidermoid, esophageal, testicular, gynecological or thyroid cancer, acute myeloid leukemia, multiple myeloma, mesothelioma, non-smal cel lung carcinoma (NSCLC), EGFR mutated or resistant lung cancer, neuroblastoma, and acute lymphoblastic leukemia (ALL); non-cancerous hyperproliferative disorders (e.g., benign hyperplasia of the skin (e.g., psoriasis), restenosis, and benign prostatic hypertrophy (BPH); and diseases related to vasculogenesis or angiogenesis (e.g., tumor angiogenesis, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer). In some embodiments, the “cel proliferative disorder” or “cancer” is lung cancer.

[0076] In stil yet other embodiments, lung cancer is an EGFR mutated or resistant lung cancer. In stil yet other embodiments, the lung cancer is NSCLC. In one embodiment, the lung cancer is EGFR mutated or resistant NSCLC. In another embodiment, the lung cancer is EGFR mutated and / or resistant NSCLC. In one embodiment, the lung cancer is EGFR mutated and resistant NSCLC which is progressing on osimertinib treatment. Non-smal cel lung cancer (NSCLC) harboring EGFR mutations typicaly arises from epithelial cels lining the airways of the lungs. EGFR-mutant lung cancer is classified based on various factors including tumor stage,Client Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 histology, and the presence of specific genetic alterations. Tumors with EGFR mutations often exhibit adenocarcinoma histology, though other histological subtypes can also harbor EGFR mutations. EGFR-mutant lung cancer is commonly categorized into subtypes such as exon 19 deletions and / or exon 21 point mutations (e.g., L858R), amongst others. These mutations are associated with increased sensitivity to EGFR tyrosine kinase inhibitors (TKIs).

[0077] Several risk factors contribute to the development of EGFR-mutant lung cancer. While smoking is a major risk factor for lung cancer, EGFR mutations are more commonly found in non-smokers or former light smokers. Other risk factors include exposure to environmental carcinogens such as radon, asbestos, and air polution.

[0078] EGFR-mutant lung cancer may present with a variety of symptoms, including cough, shortness of breath, chest pain, fatigue, unintentional weight loss, and recurent respiratory infections. Diagnostic tests commonly used for detecting EGFR-mutant lung cancer include chest X-rays, CT scans, PET scans, bronchoscopy, and biopsy for histological and molecular analysis. Staging of EGFR-mutant lung cancer is crucial for determining prognosis and treatment options, with stages ranging from I to IV. Stage I involves localized tumors, while Stage IV indicates advanced disease with distant metastasis to organs such as the brain, liver, or bones. The prognosis and treatment approach for EGFR-mutant lung cancer depends largely on the stage of the disease at diagnosis, the specific EGFR mutation subtype, and the overal health of the subject.

[0079] As used herein, the term "EGFR (Epidermal Growth Factor Receptor)" refers to a transmembrane protein receptor that plays a crucial role in cel signaling pathways regulating cel growth, proliferation, and diferentiation. EGFR is also known as ErbB1 or HER1. It belongs to the ErbB family of receptor tyrosine kinases. Various ligands, such as epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha), bind to EGFR, leading to receptor dimerization and activation of downstream signaling cascades, including the MAPK and PI3K / AKT pathways. EGFR is implicated in numerous celular processes, including cel cycle progression, angiogenesis, and metastasis. In some embodiments, EGFR mutations include, but are not limited to, Exon 19 dels, L858R, L861Q, E21 mutations, EGFR exon 20 insertions, P- loop αC-helix compression (PACC) mutations and EGFR exon T790M mutations. In one embodiment, EGFR mutations comprise Exon 19 deletions, Exon 19 insertions, E709K, G719X, S768I, V769L, T790M, L833F, L833V, V834L, H835L, L858R, A859S, K860I, L861Q, A871E,Client Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 V843I, or H870R. The EGFR protein can phosphorylate a range of substrates, including but not limited to, itself, leading to auto-phosphorylation at multiple tyrosine residues. EGFR dysregulation, often due to mutations or overexpression, is associated with various cancers, particularly lung adenocarcinoma (LUAD). In addition, EGFRs are the target of several anticancer drugs, such as EGFR tyrosine kinase inhibitors (TKIs), which are designed to inhibit EGFR activity in tumors with EGFR mutations. Preferably, EGFR herein refers to the human EGFR protein.

[0080] As used herein, the phrase “in combination” refers to use of both a selective Aurora A kinase inhibitor and a tyrosine kinase inhibitor in the treatment of the same disease or condition in the same subject, such as for the treatment of a cel proliferative disorder or cancer (e.g., lung cancer). As further described below, unless explicitly specified, the term “in combination” does not restrict the timing of administration of the selective Aurora A kinase inhibitor or the tyrosine kinase inhibitor.

[0081] In some embodiments, the phrase “in combination” refers to the use of alisertib and osimertinib in combination in the treatment of a cel proliferative disorder or cancer. In stil other embodiments, the phrase “in combination” refers to the use of alisertib and osimertinib in combination in the treatment of lung cancer. In stil further embodiments, the phrase “in combination” refers to the use of alisertib and osimertinib in combination in the treatment of EGFR mutated lung cancer. In stil further embodiments, the phrase “in combination” refers to the use of alisertib and osimertinib in combination in the treatment of NSCLC. In stil further embodiments, the phrase “in combination” refers to the use of alisertib and osimertinib in combination in the treatment of EGFR mutated NSCLC. In stil further embodiments, the phrase “in combination” refers to the use of alisertib and osimertinib in combination in the treatment of EGFR mutated and / or resistant NSCLC. In stil further embodiments, the phrase “in combination” refers to the use of alisertib and osimertinib in combination in the treatment of EGFR mutated and resistant NSCLC which is progressing on osimertinib treatment.

[0082] As used herein, the term “osimertinib”, “AZD9291”, or “Tagrisso”, as used interchangeably herein, refers to the tyrosine kinase inhibitor known as N-[2-[2- (dimethylamino)ethyl]methylamino]-4-methoxy-5-[4-(1-methyl-1H-indol-3-yl)-2- pyrimidinyl]amino]phenyl]-2-propenamide and pharmaceuticaly acceptable salts thereof. In some embodiments, the pharmaceuticaly acceptable salt is the mesylate salt of osimertinib. InClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 yet other embodiments, the osimertinib is in crystaline form. In stil other embodiments, the osimertinib is the mesylate salt of osimertinib in crystaline form, such as, for example, those described in WO 2013 / 014448, the contents of which are herein incorporated by reference.

[0083] As used herein, the phrase “pharmaceuticaly acceptable carrier” is used to refer to a material that is compatible with a recipient subject, such as a mammal, more particularly a human, and is suitable for delivering an active agent to the target site without terminating the activity of the agent. The toxicity or adverse efects, if any, associated with the carrier preferably are commensurate with a reasonable risk / benefit ratio for the intended use of the active agent.

[0084] The terms “carier”, “adjuvant”, or “vehicle” are used interchangeably herein, and include any and al solvents, diluents, and other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy.20th Ed., ed. A. Gennaro, Lippincot Wiliams & Wilkins, 2000 discloses various cariers used in formulating pharmaceuticaly acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the present disclosure, such as by producing any undesirable biological efect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceuticaly acceptable composition, its use is contemplated to be within the scope of this disclosure. Some examples of materials which can serve as pharmaceuticaly acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, bufer substances such as disodium hydrogen phosphate, potassium hydrogen phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium hydroxide and aluminum hydroxide, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable faty acids, water, pyrogen-free water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts, coloidal silica, magnesium trisilicate, polyvinyl pyrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose, sucrose, starches such as corn starch and potato starch, celulose and its derivatives such as sodium carboxymethyl celulose, ethyl celulose and celulose acetate, powdered tragacanth; malt, gelatin, talc, excipients such as cocoa buter and suppository waxes, oils such as peanut oil,Client Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 cotonseed oil, saflower oil, sesame oil, olive oil, corn oil and soybean oil, glycols such as propylene glycol and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, alginic acid, isotonic saline, Ringer's solution, alcohols such as ethanol, isopropyl alcohol, hexadecyl alcohol, and glycerol, cyclodextrins, lubricants such as sodium lauryl sulfate and magnesium stearate, petroleum hydrocarbons such as mineral oil and petrolatum. Coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0085] As used herein, the terms “p53 gene” or “p53” or “TP53” refers to a gene that encodes a protein found in nucleus of a cel known as “tumor protein p53” (or p53). The p53 gene is the most mutated gene in human cancers. Loss of function mutations in p53 can occur in the DNA- binding core domain and result in the inability of p53 to bind its target DNA sequences and thus prevent transcription of those genes. Most cancer mutations are missense mutations in the DNA- binding core. In addition, N-terminal and C-terminal truncation mutations have also been associated with cancer. p53 isoforms and mutations are described in "p53 Isoforms and Their Implications in Cancer," Vieler M et al, Cancers (Basel), 2018 Sep; 10(9): 288. Mutations in p53 in AML patients are described in "TP53 Mutations in Newly Diagnosed Acute Myeloid Leukemia," Kadia TM et al, Cancer, 2016. p53 mutations can be grouped into various classes, such as early stop codon (C-terminal truncation), N-terminal domain deletion truncation, missense or hotspot mutations that compromise function, nonsense mutations, frameshift mutations, intronic mutations, mutations in the DNA binding domain (amino acid residues 98- 293), and mutations in the tetramerization domain (amino acid residues 326-353).

[0086] Tumor protein 53 (TP53, UNIPROT P04637, NCBI Gene ID: 7157, NG_017013.2, p53 isoform a: NM_000546.6) is a tumor suppressor protein that plays a crucial role in cel cycle regulation and apoptosis after celular stress. A major role of p53 protein is at the G1 / S regulation point during cel division. After celular stress that results in DNA damage, the p53 protein is activated and initiates transcription of p53 responsive genes. p53 can activate DNA repair proteins, arest cel growth by holding the cel cycle at the G1 / S point to alow DNA repair proteins time to repair any damaged DNA, and initiate apoptosis if the DNA damage is ireparable. This alows the cel to maintain genetic stability. The p53 gene can create 12 diferent isoforms via multiple promoters, alternative slicing, and an internal ribosome entry site.Client Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101

[0087] As used herein, the phrase, “pharmaceuticaly acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects (e.g., humans and other mammals) without undue toxicity, iritation, alergic response and the like, and are commensurate with a reasonable benefit / risk ratio. In some embodiments, if a pharmaceuticaly acceptable salt of the selective inhibitor of Aurora A kinase and / or tyrosine kinase inhibitor is utilized in pharmaceutical compositions, the salt preferably is derived from an inorganic or organic acid or base. For reviews of suitable salts, see, e.g., Berge et al, J. Pharm. Sci.66:1-19 (1977) and Remington: The Science and Practice of Pharmacy.20th Ed., ed. A. Gennaro, Lippincot Wiliams & Wilkins, 2000. Examples of suitable acid addition salts include the folowing: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, mesylate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.

[0088] Suitable base addition salts include, without limitation, ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine, N-methyl-D-glucamine, t- butylamine, ethylene diamine, ethanolamine, and choline, and salts with amino acids such as arginine, lysine, and so forth.

[0089] Also, basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides, and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.

[0090] As used herein, the term " tyrosine kinase inhibitor" or “TKI” refers to a class of pharmaceutical agents designed to inhibit the activity of tyrosine kinases, enzymes that phosphorylate tyrosine residues on proteins. TKIs exert their inhibitory effects by binding to the ATP-binding pocket of tyrosine kinases, thereby preventing ATP from binding and subsequent phosphorylation of target proteins. TKIs are particularly efective against receptor tyrosineClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 kinases (RTKs), including but not limited to, EGFR (Epidermal Growth Factor Receptor), which play crucial roles in cel signaling pathways regulating cel growth, proliferation, and diferentiation. In some embodiments, the TKI includes but are not limited to, EGFRs, such as, first-generation EGFR TKIs: Erlotinib (Tarceva) and Gefitinib (Iressa), second-generation EGFR TKIs: Afatinib (Gilotrif) and Dacomitinib (Vizimpro), third-generation EGFR TKIs: osimertinib (Tagrisso) and Nazartinib, ALK (Anaplastic Lymphoma Kinase) TKIs, such as, Crizotinib (Xalkori), Ceritinib (Zykadia), Alectinib (Alecensa), Brigatinib (Alunbrig), ROS1 TKIs, such as, Crizotinib (Xalkori), Entrectinib (Rozlytrek), RET TKIs, such as, Selpercatinib (Retevmo), Pralsetinib (Gavreto), MET TKIs, such as, Crizotinib (Xalkori) and Capmatinib (Tabrecta).

[0091] As used herein, the phrase “prophylacticaly effective” or “prophylactic efect” refers to a benefit including, but not limited to, the prophylaxis of symptoms of a cel proliferative disorder or cancer (e.g., lung cancer) discussed herein. A person skiled in the art would understand that the prophylacticaly efective amount or the amount of agent required to provide a prophylactic efect wil vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being prevented (e.g., nature of the severity of the condition to be prevented, the particular inhibitor, the route of administration and the age, weight, general health, and response of the individual patient), which can be readily determined by a person of skil in the art. For example, an amount of a selective inhibitor of Aurora A kinase in combination with an amount of a tyrosine kinase inhibitor is prophylacticaly efective if it is suficient to efect the prophylaxis of symptoms of a cel proliferative disorder or cancer (e.g., lung cancer) as discussed herein.

[0092] As used herein, the terms "subject" and "patient" are used interchangeably irespective of whether the subject has or is curently undergoing any form of treatment. As used herein, the terms "subject" and "subjects" may refer to any vertebrate, including, but not limited to, a mammal (e.g., cow, pig, camel, lama, horse, goat, rabbit, sheep, hamsters, guinea pig, cat, dog, rat, and mouse, a non-human primate (for example, a monkey, such as a cynomolgus or rhesus monkey, chimpanzee, etc.) and a human). In some embodiments, the subject may be a human or a non-human. In some embodiments, the subject may be a human patient at risk for developing or already having cancer such as, for example, lung cancer or NSCLC lung cancer. In some embodiments, the subject is a previously treated lung cancer or NSCLC subject. In some embodiments, the lung cancer or NSCLC subject has been treated previously with at least oneClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 additional line of systemic cancer therapy other than osimertinib. In some embodiments, the lung cancer or NSCLC subject has been treated previously with no more than one additional line of systemic cancer therapy other than osimertinib. In some such embodiments, the additional line of systemic cancer therapy other than osimertinib may be, for example, chemotherapy + / - osimertinib, immunotherapy, bevacizumab, or amivantamab + / - lazertinib, or chemotherapy.

[0093] In some embodiments, the lung cancer or NSCLC subject has been treated previously with osimertinib. In some embodiments, the lung cancer or NSCLC subject is curently being treated with an EGFR TKI, such as curently being treated with osimertinib. In some embodiments, the lung cancer or NSCLC subject is curently being treated with an EGFR TKI, such as currently being treated with osimertinib mesylate. In some embodiments, the lung cancer or NSCLC subject is an EGFR-TKI resistant NSCLC subject, such as an osimertinib- resistant NSCLC subject. In some embodiments, the subject is a lung cancer or NSCLC subject in remission. In some embodiments, the lung cancer or NSCLC subject has early stage lung cancer or NSCLC, metastatic lung cancer or NSCLC, advanced lung cancer or NSCLC, relapsed lung cancer or NSCLC, or refractory lung cancer or NSCLC. In some embodiments, the lung cancer or NSCLC subject has early stage lung cancer or NSCLC. In some embodiments, the lung cancer or NSCLC subject has metastatic lung cancer or NSCLC or advanced lung cancer or NSCLC. In some embodiments, the lung cancer or NSCLC subject has relapsed lung cancer or NSCLC or refractory lung cancer or NSCLC. In some embodiments, the lung cancer or NSCLC subject has been treated previously with osimertinib and is resistant to osimertinib. In some such embodiments, the lung cancer or NSCLC subject has metastatic lung cancer or NSCLC or advanced lung cancer or NSCLC. In some embodiments, the metastatic lung cancer subject has been treated previously with osimertinib and is resistant to osimertinib. In some embodiments, the metastatic NSCLC subject has been treated previously with osimertinib and is resistant to osimertinib. In some embodiments, the advanced lung cancer subject has been treated previously with osimertinib and is resistant to osimertinib. In some embodiments, the advanced NSCLC subject has been treated previously with osimertinib and is resistant to osimertinib.

[0094] The phrase “therapeuticaly efective” and “therapeutic efect” refer to a benefit including, but not limited to, the treatment or amelioration of symptoms of a cel proliferative disorder, such as cancer (e.g., lung cancer), discussed herein. It wil be appreciated that the therapeuticaly efective amount or the amount of one or more agents required to provide aClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 therapeutic efect wil vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., nature of the severity of the condition to be treated, the particular inhibitor, the route of administration and the age, weight, general health, and response of the individual subject), which can be readily determined by a person of skil in the art. For example, an amount of a selective inhibitor of Aurora A kinase in combination with an amount of a tyrosine kinase inhibitor is therapeuticaly efective if it is suficient to effect the treatment or amelioration of symptoms of a cel proliferative disorder or cancer (e.g., lung cancer) as discussed herein. In some embodiments, the therapeutic benefit provided by the methods of treating disclosed herein includes, but is not limited to, increasing one or more of Time To Progression (TTP), disease control rate (DCR), Progression Free Survival (PFS), Event-free survival (EFS), Overal Survival (OS), overal response rate (ORR), and depth of response (DoR). In some embodiments, a selective inhibitor of Aurora A kinase in combination with a tyrosine kinase inhibitor described here, achieves one or more of secondary points including Time To Progression (TTP), disease control rate (DCR) for at least 12 weeks, Progression Free Survival (PFS), Event-free survival (EFS), Overal Survival (OS), overal response rate (ORR) by RECIST 1.1 criteria, and duration of response (DoR). In some such embodiments, the selective inhibitor of Aurora A kinase is alisertib. In some such embodiments, the tyrosine kinase inhibitor is osimertinib.

[0095] As used herein, whether by themselves or in conjunction with another term or terms, "treats," "treating," "treated," and "treatment," refer to and include ameliorative, paliative, and / or curative uses and results, or any combination thereof. In other embodiments, the methods described herein can be used prophylacticaly, that is, preventatively. It should be understood that "prophylaxis" or a prophylactic use or result do not refer to nor require absolute or total prevention (i.e., a 100% preventative or protective use or result). As used herein, prophylaxis or a prophylactic (preventative) use or result refers to uses and results in which administration of a compound, therapeutic agent or composition diminishes or reduces the severity of a particular condition, symptom, disorder, or disease described herein; diminishes or reduces the likelihood of experiencing a particular condition, symptom, disorder, or disease described herein; or delays the onset or relapse (reoccurrence) of a particular condition, symptom, disorder, or disease described herein; or any combination of the foregoing.Client Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 1. Use of Serine Kinase Inhibitors and Selective Aurora A Kinase Inhibitors for Treating Cel Proliferative Disorders or Cancer

[0096] Provided herein are methods and kits for use in treatment of a cel proliferative disorder or cancer in a subject. In some embodiments, the methods and kits described herein can be used in the treatment of lung cancer in a subject. In other embodiments, the methods and kits described herein can be used in the treatment of EGFR mutated lung cancer in a subject. In stil yet other embodiments, the methods and kits described herein can be used in the treatment of NSCLC in a subject. In some embodiments, the methods and kits described herein can be used in the treatment of EGFR mutated NSCLC in a subject. The methods described herein involve administering to a subject in need of treatment thereof a therapeuticaly effective amount of a combination of a tyrosine kinase inhibitor and a selective Aurora A kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor and selective Aurora A kinase inhibitor can be administered simultaneously or sequentialy, in any order. In stil further embodiments, the tyrosine kinase inhibitor is osimertinib or a pharmaceuticaly acceptable salt thereof and the selective Aurora A kinase inhibitor is alisertib or a pharmaceuticaly acceptable salt thereof.

[0097] The therapeuticaly effective amounts or suitable dosages of tyrosine kinase inhibitor and selective Aurora A kinase inhibitor to be administered to a subject wil depend upon a number of factors, including the nature of the severity of the condition to be treated, the particular inhibitor used, the route of administration, and the age, weight, general heath, and response of the individual subject. Such therapeuticaly effective amounts or suitable dosages to be administered to a subject can be determined using routine techniques in the art.

[0098] In some embodiments, the therapeuticaly effective amounts or suitable dosages of tyrosine kinase inhibitor and the selective Aurora A kinase inhibitor are administered to a subject suffering from lung cancer. In some embodiments, the lung cancer is an EGFR mutated lung cancer. In stil other embodiments, the lung cancer is NSCLC. In stil other embodiments, the subjects suffering from lung cancer is administered a therapeuticaly effective amount or suitable dosage of a combination of osimertinib or pharmaceuticaly acceptable salt thereof and alisertib or a pharmaceuticaly acceptable salt thereof. In some embodiments, the lung cancer is an EGFR mutated lung cancer. In stil other embodiments,Client Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 the lung cancer is NSCLC. In some embodiments, the lung cancer is an EGFR mutated NSCLC.

[0099] In some embodiments, the therapeuticaly effective amount or suitable dosage of osimertinib that can be administered to a subject suffering from lung cancer is about 20 mg to about 100 mg. In some embodiments, the dose of osimertinib is from about 20 mg to about 80 mg. In some embodiments, the dose of osimertinib is from about 40 mg to about 80 mg. In some embodiments, the dose of osimertinib is from about 60 mg to about 80 mg. In some embodiments, the dose of osimertinib is about 20 mg. In some embodiments, the dose of osimertinib is about 40 mg. In some embodiments, the dose of osimertinib is about 60 mg. In further embodiments, the dose of osimertinib is about 80 mg. In some embodiments, the dose of osimertinib is about 100 mg. The osimertinib administered to a subject can be administered daily, once, or twice per day, in single or divided doses.

[0100] In some embodiments, the therapeuticaly efect amount or suitable dosage of alisertib that can be administered to a subject sufering from lung cancer is from about 10 mg to about 200 mg. In some embodiments, dose of alisertib is from about 20 mg to about 160 mg. In some embodiments, the dose of alisertib is from about 30 to about 100 mg. In stil other embodiments, the dose of alisertib is from about 30 to about 80 mg. The alisertib administered to a subject can be administered daily, once or twice per day, in single or divided doses. Thus, in some embodiments, when administered twice per day (e.g., twice-daily dose), each dose of alisertib administered to a subject is from about 5 mg to about 100 mg (e.g., for a total daily dose of from about 10 to about 200 mg). In some embodiments, each dose of alisertib administered to a subject twice a day is from about 10 mg to about 80 mg (e.g., for a total daily dose of from about 20 mg to about 160 mg). In some embodiments, each dose of alisertib administered to a subject twice a day (e.g., twice daily) is from about 15 mg to about 50 mg (e.g., for a total daily dose of from about 30 mg to about 100 mg). In some embodiments, each dose of alisertib administered to a subject twice a day is from about 20 mg to about 50 mg (e.g., for a total daily dose of about 40 mg to about 100 mg). In some embodiments, each dose of alisertib administered to a subject twice a day is from about 30 mg to about 50 mg (e.g., for a total daily dose of about 60 mg to about 100 mg). In some embodiments, the twice-daily dose of alisertib is from about 30 mg to about 40 mg (e.g., for a total daily dose of about 60 mg to about 80 mg). In some embodiments, the twice-daily dose of alisertib is about 30 mg (e.g., for aClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 total daily dose of 60 mg). In some embodiments, the twice-daily dose of alisertib is about 35 mg (e.g., for a total daily dose of 70 mg). In some embodiments, the twice-daily dose of alisertib is about 40 mg (e.g., for a total daily dose of 80 mg). In some embodiments, the twice- daily dose of alisertib is about 50 mg (e.g., for a total daily dose of 100 mg).

[0101] In some embodiments, the osimertinib and alisertib are cyclicaly administered to a subject. Cycling therapy involves the administration of a first agent (e.g., a first prophylactic or therapeutic agents) for a period of time, folowed by the administration of a second agent and / or third agent (e.g., a second and / or third prophylactic or therapeutic agents) for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and / or improve the eficacy of the treatment.

[0102] In some embodiments, the treatment period during which an agent is administered is folowed by a non-treatment period of a particular time duration, during which therapeutic agents are not administered to the subject. This non-treatment period can then be folowed by a series of subsequent treatment and non-treatment periods of the same or diferent frequencies for the same or diferent lengths of time. In some embodiments, the treatment and non-treatment periods are alternated. It wil be understood that the period of treatment in cycling therapy may continue until the subject has achieved a complete response or a partial response, at which point the treatment may be stopped. Alternatively, the period of treatment in cycling therapy may continue until the subject has achieved a complete response or a partial response, at which point the period of treatment may continue for a particular number of cycles. In some embodiments, the length of the period of treatment may be a particular number of cycles, regardless of subject response. In some other embodiments, the length of the period of treatment may continue until the subject relapses.

[0103] For example, in some embodiments, from about 10 mg to about 100 mg of alisertib (e.g., for a total daily dose of 20 mg to about 200 mg) can be administered to a subject sufering lung cancer twice daily for 3 days (e.g., a first treatment period) folowed by 4 days of non- treatment (e.g., first non-treatment period) folowed by 3 days of twice daily administration (e.g., second treatment period), folowed by another 4 days of non-treatment (e.g., second non- treatment period). In some embodiments, the treatment and non-treatment periods are alternated. The second treatment period can be folowed by other treatment periods. During the treatmentClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 and non-treatment periods, a therapeuticaly efective amount of osimertinib is administered daily to the subject.

[0104] In some embodiments, the administration is on a 28-day dose cycle in which osimertinib is administered once daily (days 1-28) concomitantly with alisertib which is administered twice-daily on a schedule of 3 days on folowed by 4 days of which is repeated once (e.g., the osimertinib is administered daily for 28 days and the alisertib is administered to the subject on days 1, 2, 3, 8, 9, 10, 15, 16 and 17). In such a 28-day dosing cycle, the order in which the osimertinib and alisertib is administered is not critical.

[0105] In stil further embodiments, a subject suffering from lung cancer and on a 28-day dose schedule is administered a daily dose of osimertinib in combination with a twice-daily dose of alisertib. Specificaly, osimertinib is administered daily to the subject, on days 1-28, in an amount of from about 20 mg to about 240 mg. In some embodiments, the daily dose of osimertinib administered to the subject is about 80 mg (e.g., for days 1-28). The alisertib is administered twice daily to the subject on days 1-3, 8-10, and 15-17 of the 28-day schedule in an amount from about 30 mg to about 50 mg (e.g., for a total daily dose of about 60 mg to about 100 mg). In some embodiments, the alisertib is administered twice daily to the subject on days 1-3, 8-11, and 15-17 of the 28-day schedule in an amount from about 30 mg to about 50 mg (e.g., for a total daily dose of about 60 mg to about 100 mg). In some embodiments, the twice daily dose of alisertib administered to the subject is from about 30 mg to about 40 mg (for a total daily dose of about 60 mg or about 80 mg). In some embodiments, the administration of alisertib is simultaneous with the administration of osimertinib, which can be in any order. In other embodiments, the administration of alisertib is successive with the administration of osimertinib, which can be in any order. In some embodiments, the lung cancer is EGFR mutated lung cancer. In other embodiments, the lung cancer is NSCLC. In some embodiments, the lung cancer is an EGFR mutated NSCLC.

[0106] In some embodiments, the administering to a subject sufering from lung cancer a daily dose of osimertinib in combination with a twice-daily dose alisertib pursuant to the above- described 28-day schedule results in a disease control rate of about 70%. In some embodiments, the administering to a subject a daily dose of osimertinib in combination with a twice-daily dose of alisertib pursuant to the above-described 28-day schedule results in a disease control rate of about 75%. In some embodiments, the administering to a subject a daily dose of osimertinib inClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 combination with a twice-daily dose alisertib pursuant to the above-described 28-day schedule results in a disease control rate of about 80%. In some embodiments, the administering to a subject a daily dose of osimertinib in combination with a twice-daily dose of alisertib pursuant to the above-described 28-day schedule results in a disease control rate of about 85%. In some embodiments, the administering to a subject a daily dose of osimertinib in combination with a twice-daily dose of alisertib pursuant to the above-described 28-day schedule results in a disease control rate of about 90%. In some embodiments, the administering to a subject a daily dose of osimertinib in combination with a twice-daily dose of alisertib pursuant to the above- described 28-day schedule results in a disease control rate of about 95%. In some embodiments, the administering to a subject a daily dose of osimertinib in combination with a twice-daily dose of alisertib pursuant to the above-described 28-day schedule results in a disease control rate of about 99%.

[0107] The term “disease control rate (DCR)” is used herein to describe a metric to gauge the overal efectiveness of a treatment in controling the progression of a disease. In some embodiments, the DCR is calculated as the portion of a subject who achieved either a complete response (CR), partial response (PR), or stable disease (SD) as defined by predetermined criteria. In some embodiments, the predetermined criteria is the Response Evaluation Criteria in Solid Tumors (RECIST).

[0108] The osimertinib and alisertib can be administered by any methods known to one skiled in the art. For example, each of the osimertinib and alisertib can be administered in the form of a composition, such as, for example, a pharmaceutical composition of osimertinib and / or alisertib and a pharmaceuticaly acceptable carier, such as those described herein. The pharmaceutical compositions of osimertinib and / or alisertib can be provided as separate pharmaceutical compositions or together, as a single fixed dose combination composition. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the pharmaceutical composition is a tablet for oral administration, such as an enteric coated tablet. Such tablets are described in U.S. Publication No.2010 / 0310651, which is hereby incorporated by reference in its entirety. In some other embodiments, the pharmaceutical composition is a liquid dosage form for oral administration. Such liquid dosage forms are described in U.S. Publication No.2011 / 0039826, which is hereby incorporated by reference. InClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 some embodiments, these compositions optionaly further comprise one or more additional therapeutic agents.

[0109] The pharmaceutical compositions described herein can be manufactured by methods wel known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, or emulsifying processes, among others. Compositions may be produced in various forms, including granules, precipitates, or particulates, powders, including freeze dried, rotary dried or spray dried powders, amorphous powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. Formulations may optionaly contain solvents, diluents, and other liquid vehicles, dispersion or suspension aids, surface active agents, pH modifiers, isotonic agents, thickening or emulsifying agents, stabilizers and preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.

[0110] In some embodiments, pharmaceutical compositions are formulated for pharmaceutical administration to a mammal, preferably a human being. Such pharmaceutical compositions may be administered oraly, parenteraly, by inhalation spray, topicaly, rectaly, nasaly, buccaly, vaginaly or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered oraly, intravenously, or subcutaneously. The formulations of the present disclosure may be designed to be short-acting, fast-releasing, or long- acting. Stil further, compounds can be administered in a local rather than systemic means, such as administration (e.g., by injection) at a tumor site.

[0111] Liquid dosage forms for oral administration include, but are not limited to, pharmaceuticaly acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, cyclodextrins, dimethylformamide, oils (in particular, cotonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and faty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also includeClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 adjuvants such as weting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0112] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or weting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenteraly acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionaly employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, faty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. Compositions formulated for parenteral administration may be injected by bolus injection or by timed push or may be administered by continuous infusion.

[0113] In order to prolong the effect of a compound or therapeutic agent (e.g., osimertinib and / or alisertib), it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystaline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystaline form. Alternatively, delayed absorption of a parenteraly administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0114] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the osimertinib and / or alisertib with suitable non-iritating excipientsClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 or carriers such as cocoa buter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0115] Solid dosage forms for oral administration include capsules, tablets, pils, powders, and granules. In such solid dosage forms, the therapeutic agent is mixed with at least one inert, pharmaceuticaly acceptable excipient or carier such as sodium citrate or dicalcium phosphate and / or a) filers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcelulose, alginates, gelatin, polyvinylpyrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as parafin, f) absorption accelerators such as quaternary ammonium compounds, g) weting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pils, the dosage form may also comprise bufering agents such as phosphates or carbonates.

[0116] Solid compositions of a similar type may also be employed as filers in soft and hard- filed gelatin capsules using such excipients as lactose or milk sugar as wel as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pils, and granules can be prepared with coatings and shels such as enteric coatings and other coatings wel known in the pharmaceutical formulating art. They may optionaly contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentialy, in a certain part of the intestinal tract, optionaly, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as filers in soft and hard-filed gelatin capsules using such excipients as lactose or milk sugar as wel as high molecular weight polyethylene glycols and the like.

[0117] The osimertinib and / or alisertib can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pils, and granules can be prepared with coatings and shels such as enteric coatings, release controling coatings and other coatings wel known in the pharmaceutical formulating art. In such solidClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystaline celulose. In the case of capsules, tablets and pils, the dosage forms may also comprise buffering agents. They may optionaly contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentialy, in a certain part of the intestinal tract, optionaly, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0118] Dosage forms for topical or transdermal administration of the therapeutic agents described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceuticaly acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionaly, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controled by either providing a rate controling membrane or by dispersing the compound in a polymer matrix or gel.

[0119] Compositions for use in the method of the present disclosure may be formulated in unit dosage form for ease of administration and uniformity of dosage. The phrase “unit dosage form” as used herein refers to a physicaly discrete unit of agent appropriate for the subject to be treated. It wil be understood, however, that the total daily usage of the compounds and pharmaceutical compositions described herein wil be decided by the atending physician within the scope of sound medical judgment. A unit dosage form for parenteral administration may be in ampoules or in multi-dose containers.

[0120] The present disclosure is also directed to kits and other articles of manufacture for treating a cel proliferative disease or cancer, such as, for example, lung cancer. In one embodiment, a kit is provided that comprises osimertinib or a pharmaceuticaly acceptable salt thereof, alisertib or a pharmaceuticaly acceptable salt thereof and instructions. The kit may optionaly further include one or more additional therapeutic agents, as described herein. TheClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 instructions may indicate the disease state for which the kit is to be used, storage information, dosing information and / or instructions regarding how to administer the osimertinib, alisertib, and / or additional therapeutic agent or agents. The kit may also comprise packaging materials. The packaging material may comprise a container for housing the contents of the kit. The kit may also optionaly comprise additional components, such as syringes for administration of the contents of the kit. The kit may comprise the osimertinib, alisertib, and / or additional therapeutic agent or agents in single or multiple dose forms.

[0121] In another embodiment, an article of manufacture is provided that comprises the osimertinib or a pharmaceuticaly acceptable salt thereof, alisertib or a pharmaceuticaly acceptable salt thereof and packaging materials. The article of manufacture may optionaly further include the one or more additional therapeutic agents. The packaging material may comprise a container for housing the contents of the article of manufacture. The container may optionaly comprise a label indicating the disease state for which the article is to be used, storage information, dosing information and / or instructions regarding how to administer the osimertinib, alisertib, and / or additional therapeutic agent or agents. The article may also optionaly comprise additional components, such as syringes for administration of the composition. The article may comprise the osimertinib, alisertib and / or additional therapeutic agent or agents in single or multiple dose forms.

[0122] A wide variety of therapeutic agents may have a therapeuticaly relevant added benefit in combination with the combination of osimertinib and alisertib as described herein. Combination therapies that comprise the combination of osimertinib and alisertib and together with one or more other therapeutic agents can be used, for example, to: 1) enhance the therapeutic efect(s) of the methods of the present disclosure and / or the one or more other therapeutic agents (e.g., osimertinib and alisertib); 2) reduce the side efects exhibited by the methods of the present disclosure and / or the one or more other therapeutic agents (e.g., osimertinib and alisertib); and / or 3) reduce the efective dose of osimertinib and alisertib used in the methods described herein and / or the one or more other therapeutic agents.

[0123] In some embodiments, the methods of the present disclosure further comprise administering to a subject in need thereof (e.g., a subject sufering lung cancer), a therapeuticaly efective amount of an additional therapeutic agent in addition to the combination of osimertinib and alisertib.Client Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101

[0124] For example, in certain embodiments, osimertinib and alisertib can be administered with the concomitant or sequential administration of cisplatin or doxorubicin. It wil be appreciated that the combination therapy includes administration of therapeutic agents concurently or sequentialy. Alternatively, the therapeutic agents can be combined into one composition which is administered to the subject.

[0125] Examples of other therapeutic agents that may be used in combination with the combination of osimertinib and alisertib, include, but are not limited to, anti-proliferative agents, anticancer agents, antimetabolic agents, and biologic agents.

[0126] Antimetabolic agents are a group of drugs that interfere with metabolic processes vital to the physiology and proliferation of cancer cels. Actively proliferating cancer cels require continuous synthesis of large quantities of nucleic acids, proteins, lipids, and other vital celular constituents. Many of the antimetabolites inhibit the synthesis of purine or pyrimidine nucleosides or inhibit the enzymes of DNA replication. Some antimetabolites also interfere with the synthesis of ribonucleosides and RNA and / or amino acid metabolism and protein synthesis as wel. By interfering with the synthesis of vital celular constituents, antimetabolites can delay or arrest the growth of cancer cels. Examples of antimetabolic agents include, but are not limited to, pemetrexed, capecitabine, fluorouracil (5-FU), floxuridine (5-FUdR), methotrexate, leucovorin, hydroxyurea, thioguanine (6-TG), mercaptopurine (6-MP), cytarabine, fludarabine phosphate, cladribine (2-CDA), and gemcitabine. Combination therapy including osimertinib and / or alisertib as described herein and an antimetabolic agent may have therapeutic synergistic efects on cancer and reduce sides affects associated with these chemotherapeutic agents.

[0127] Biologic agents are a group of biomolecules that elicit cancer / tumor regression when used alone or in combination with chemotherapy and / or radiotherapy. Examples of biologic agents include, but are not limited to, immunomodulating proteins such as cytokines, monoclonal antibodies against tumor antigens, tumor suppressor genes, and cancer vaccines.

[0128] Combination therapy including an inhibitor of the present disclosure and a biologic agent may have therapeutic synergistic effects on cancer, enhance the subject’s immune responses to tumorigenic signals, and reduce potential sides affects associated with this chemotherapeutic agent.

[0129] Cytokines that may be used in conjunction with the inhibitors of the present disclosure include those cytokines that exert profound efects on hematopoiesis and immuneClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 functions. Examples of such cytokines include, but are not limited to erythropoietin, granulocyte-CSF (filgrastin), and granulocyte, macrophage-CSF (sargramostim). These cytokines may be used in conjunction with an inhibitor of the present disclosure to reduce chemotherapy-induced myelopoietic toxicity.

[0130] Monoclonal antibodies against tumor antigens are antibodies elicited against antigens expressed by tumors, preferably tumor-specific antigens. For example, monoclonal antibodies include, but are not limited to, Pembrolizumab (Keytruda), nivolumab (Opdivo), atezolizumab (Tecentriq), durvalumab (Imfinzi), Angiogenesis inhibitors such as, Bevacizumab (Avastin), EGFR inhibitors such as, Cetuximab (Erbitux), necitumumab (Portrazza), MET inhibitors such as, Onartuzumab targeted therapies such as, Ramucirumab, Tislelizumab, camrelizumab, sintilimab. Combination therapy including osimertinib and alisertib as described herein and monoclonal antibodies may have therapeutic synergistic effects on cancer and reduce sides efects associated with these chemotherapeutic agents.

[0131] Tumor Suppressor genes are genes that function to inhibit cel growth and division cycles, thus preventing the development of neoplasia. Mutations in tumor suppressor genes cause the cel to ignore one or more of the components of the network of inhibitory signals, overcoming the cel cycle checkpoints and resulting in a higher rate of controled cel growth- cancer. Examples of the tumor suppressor genes include, but are not limited to, EGFR, ALK, ROS1, KRAS, BRAF, TP53, STK11 (LKB1), MET, RET, ERBB2 (HER2), PIK3CA, FGFR1, DDR2, NRAS, NTRK1-3, PTEN, CDKN2A, MAP2K1, SMARCA4, KEAP1. Combination therapy including a combination of osimertinib, and alisertib as described herein and a tumor suppressor may have therapeutic synergistic efects on subjects sufering from various cancer, such as lung cancer.

[0132] An adjuvant may be used to augment the immune response to tumor-associated antigens (TAAS). Examples of adjuvants include, but are not limited to, chemotherapy such as, platinum-based chemotherapy regimens, such as cisplatin or carboplatin combined with drugs like vinorelbine, paclitaxel, or docetaxel, targeted therapies, such as, EGFR mutations and ALK inhibitors, Immunotherapies, such as, PD-L1, radiation therapies, combined modality therapies. 2. Selecting Subjects for Treatment with a Combination of a Serine Kinase Inhibitor and a Selective Aurora A Kinase InhibitorClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101

[0133] Provided herein are methods for selecting subjects suffering from a cel proliferative disorder or cancer (e.g., lung cancer) for treatment with a combination of a serine kinase inhibitor and a selective Aurora A kinase inhibitor. In some embodiments, provided are methods for selecting subjects suffering from lung cancer for treatment with a combination of osimertinib or a pharmaceuticaly acceptable salt thereof and alisertib or a pharmaceuticaly acceptable salt thereof as described previously herein in Section 1. In some embodiments, the lung cancer is EGFR mutated lung cancer. In other embodiments, the lung cancer is NSCLC. In some embodiments, the lung cancer is an EGFR mutated NSCLC.

[0134] The first step of the method involves receiving information on the number of mutations in a p53 gene in a biological sample obtained from a subject sufering from a cel proliferative disorder or cancer, such as, for example, lung cancer. In some embodiments, the biological sample is obtained from a subject suffering from lung cancer, such as, EGFR mutated lung cancer or NSCLC. In some embodiments, the lung cancer is an EGFR mutated NSCLC.

[0135] In some embodiments, the biological sample obtained from a subject sufering from lung cancer is a liquid sample, a tumor biopsy sample, a tissue biopsy sample, a bone marrow sample, or a combination thereof. In further embodiments, the liquid sample, is a whole blood sample, a plasma sample, a serum sample, a urine sample, a pleural fluid or ascites sample, a lymph sample, a peritoneal fluid sample, a saliva sample, a cerebrospinal fluid sample, a stool sample, or any combinations thereof. In yet other embodiments, the tumor biopsy sample is a needle biopsy sample, a transbronchial biopsy sample, a thoracoscopic biopsy or an open biopsy sample.

[0136] Once a biological sample is obtained from a subject (e.g., sufering from lung cancer), the number of mutations in the p53 gene is determined using routine techniques known in the art. In some aspects, the number of mutations in the p53 gene can be determined using one or more sequencing assays. Examples of sequencing assays that can be used in the methods described herein include: whole genome sequencing (WGS), whole exome sequencing (WES), targeted sequencing, next generation sequencing, RNA sequencing (RNA-Seq), chromatin immunoprecipitation sequencing (ChIP-Seq), single-cel sequencing, or any combination thereof.

[0137] Once the number of mutations in the p53 gene is determined, the next step of the method involves making a decision of whether to select the subject for treatment with a combination of osimertinib or a pharmaceuticaly acceptable salt thereof and alisertib or aClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 pharmaceuticaly acceptable salt thereof as described previously herein in Section 1. Specificaly, in some aspects, a subject is selected for treatment with a combination of osimertinib or a pharmaceuticaly acceptable salt thereof and alisertib or a pharmaceuticaly acceptable salt thereof as described previously herein in Section 1 if no mutations are identified in the p53 gene (e.g., the subject contains the wildtype p53 gene). In other aspects, a subject is not selected for treatment with a combination of osimertinib or a pharmaceuticaly acceptable salt thereof and alisertib or a pharmaceuticaly acceptable salt thereof as described previously herein in Section 1 if one or more mutations are identified in the p53 gene. In some embodiments, if pursuant to the above method, a determination is made that the subject is to be selected for treatment with a combination of osimertinib or a pharmaceuticaly acceptable salt thereof and alisertib or a pharmaceuticaly acceptable salt thereof, the subject is administered a therapeuticaly efective amount of the combination as described previously herein in Section 1. In other embodiments, if pursuant to the above method, a determination is made that the subject is not to be selected for treatment with a combination of osimertinib or a pharmaceuticaly acceptable salt thereof and alisertib or a pharmaceuticaly acceptable salt thereof, the subject can be administered one or more therapeutic agents other than osimertinib and / or alisertib. 3. Methods of Monitoring Subjects Receiving Treatment with a Combination of Serine Kinase Inhibitor and a Selective Aurora A Kinase Inhibitor

[0138] In other embodiments, also provided herein are methods of monitoring a subject sufering from a cel proliferative disorder or cancer (e.g., lung cancer) and receiving treatment with a combination of a serine kinase inhibitor and a selective Aurora A kinase Inhibitor as described in Section 1. In some embodiments, the methods involve monitoring a subject sufering from lung cancer and receiving treatment with a combination of osimertinib or a pharmaceuticaly acceptable salt thereof and alisertib or a pharmaceuticaly acceptable salt thereof as described in Section 1. In some embodiments, the lung cancer is EGFR mutated lung cancer. In other embodiments, the lung cancer is NSCLC. In some embodiments, the lung cancer is an EGFR mutated NSCLC.

[0139] The first step of the method involves receiving information on the number of mutations in a p53 gene in a biological sample obtained from a subject sufering from lungClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 cancer and receiving treatment with a combination of osimertinib and alisertib as described in Section 1.

[0140] In some embodiments, the biological sample obtained from a subject sufering from lung cancer is a liquid sample, a tumor biopsy sample, a tissue biopsy sample, a bone marrow sample, or a combination thereof. In further embodiments, the liquid sample, is a whole blood sample, a plasma sample, a serum sample, a urine sample, a pleural fluid or ascites sample, a lymph sample, a peritoneal fluid sample, a saliva sample, a cerebrospinal fluid sample, a stool sample, or any combinations thereof. In yet other embodiments, the tumor biopsy sample is a needle biopsy sample, a transbronchial biopsy sample, a thoracoscopic biopsy or an open biopsy sample.

[0141] Once a biological sample is obtained from a subject (e.g., sufering from lung cancer), the number of mutations in the p53 gene is determined using routine techniques known in the art. In some aspects, the number of mutations in the p53 gene can be determined using one or more sequencing assays. Examples of sequencing assays that can be used in the methods described herein include: whole genome sequencing (WGS), whole exome sequencing (WES), targeted sequencing, next generation sequencing, RNA sequencing (RNA-Seq), chromatin immunoprecipitation sequencing (ChIP-Seq), single-cel sequencing, or any combination thereof.

[0142] Once the number of mutations in the p53 gene is determined, the next step of the method involves making a decision of whether to continue to treat the subject with a combination of osimertinib or a pharmaceuticaly acceptable salt thereof and alisertib or a pharmaceuticaly acceptable salt thereof as described previously herein in Section 1 or to stop the treatment and treat the subject with one or more different therapeutic agents (e.g., meaning other than osimertinib and / or alisertib).

[0143] Specificaly, in some aspects, treatment with the combination of osimertinib or a pharmaceuticaly acceptable salt thereof and alisertib or a pharmaceuticaly acceptable salt thereof as described previously herein in Section 1 is continued in the subject if no mutations are identified in the p53 gene (e.g., the subject contains the wildtype p53 gene) from the biological sample obtained from the subject. In other aspects, treatment with the combination of osimertinib or a pharmaceuticaly acceptable salt thereof and alisertib or a pharmaceuticaly acceptable salt thereof is stopped or if one or more mutations are identified in the p53 gene from the biological sample obtained from the subject.Client Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 EXAMPLES

[0144] The folowing examples are for the purposes of ilustration only and are not intended to limit the scope of the claims. EXAMPLE 1 METHODS

[0145] 21 total patients were treated in an open-label, single-center phase I trial (NCT04085315).10 patients were treated in a 3+3 dose escalation phase with alisertib using an intermitent dosing strategy of 30 mg (n = 6) or 40 mg (n = 4) twice daily (BID) on days (d) 1- 3, 8-10, and 15-17 of a 28-day cycle in combination with osimertinib 80 mg daily.11 additional patients were treated at the 30 mg alisertib intermitent dosing schedule in combination with osimertinib 80 mg daily in a Phase Ib dose expansion. Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase I dose (RP2D) of the alisertib and osimertinib combination. Secondary endpoints were investigator-assessed objective response rate (ORR) by RECIST 1.1 criteria, depth of response (DoR), disease control rate (DCR) for at least 12 weeks, progression-free survival (PFS) and overal survival (OS). RESULTS

[0146] 21 patients with stage IV EGFR-mutated Lung Adenocarcinoma (LUAD) (76.1% exon 19 deletion; 14.3% L858R; 9.5 % L861Q) who had progressed on osimertinib were enroled.10 (47.6%) patients had received only first-line osimertinib, while 11 (52.3%) had received > 2 lines of prior therapy. Common treatment-related adverse events were neutropenia (42.9%), anemia (42.9%), and diarrhea (38.1%). There were no treatment-related deaths. Intermitent alisertib 30 mg BID with osimertinib 80 mg daily was the MTD and R2PD. ORR for al enroled patients was 9.5% (95% CI: 1.2% to 30.4%), DCR was 81% (95% CI: 58.1% to 94.6%), and median DoR was -4 % (95% CI: -15% to 10%). The median PFS was 5.5 months (95% CI: 3.7 – 13.2 months) and median OS was 23.5 months (95% CI: 11.9 months – NR). As shown herein and in FIGS.1 and 3, intermitent dosing of alisertib 30 mg BID in combination with osimertinib 80 mg daily demonstrated no dose limiting toxicities and was identified as the RP2D. While ORR was < 10%, DCR was > 80% and the median PFS was 5.5 months. The combination of alisertib and osimertinib demonstrated an ability to control LUAD with EGFR Exon 19 deletion, L858R, and L861Q mutations (FIG.2). The median progressionClient Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 PFS (months) with 95% confidence intervals is ilustrated by the Kaplan Meier curve in FIG.3). There was no significant diference in PFS identified based on whether patients received one or two or more prior lines of therapy to treat their lung cancer (FIG.4A-4B). Treatment with prior chemotherapy also did not afect PFS (FIG.5). The objective response rate (ORR) by RECIST 1.1 criteria was 0% for patients whose tumors harbored one or more TP53 mutations (TP53MUT) and 25% for patients whose tumors did not harbor a detectable TP53 mutation (TP53WT). The disease control rate (DCR)was also greater in patients whose tumor did not harbor a detectable TP53 mutation (FIG.6A-6B). The median PFS was 3.7 months for patients whose tumors harbored one or more TP53 mutations and 8.0 months for patients whose tumors did not harbor a detectable TP53 mutation (FIG.7).

[0147] It is understood that the foregoing detailed description and accompanying examples are merely ilustrative and are not to be taken as limitations upon the scope of the disclosure, which is defined solely by the appended claims and their equivalents.

[0148] Various changes and modifications to the disclosed embodiments wil be apparent to those skiled in the art and may be made without departing from the spirit and scope thereof. EXAMPLE 2 METHODS 6-16 patients with Stage IV, EGFR-mutant, NSCLC, with no known tumor non-synonymous TP53 genomic alteration, currently receiving and progressing on osimertinib, and who have received no more than one additional line of systemic cancer therapy other than osimertinib (e.g., chemotherapy + / - osimertinib, immunotherapy, bevacizumab, or amivantamab + / - lazertinib, or chemotherapy) for metastatic disease are enroled. Patients wil receive alisertib therapy until lack of clinical benefit or intolerable toxicity. The primary endpoint of this study is ORR. Secondary endpoints include DCR, 2-year PFS, 2-year OS, and DOR as wel as toxicity. Key Inclusion Criteria: • Documented activating EGFR mutation (Exon 19 deletion, Exon 19 insertion, E709K, G719X, S768I, V769L, T790M, L833F, L833V, V834L, H835L, L858R, A859S, K860I, L861Q, A871E, V843I, or H870R) on tumor sample or cel-free DNA sample performed in CLIA-approved laboratory.Client Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 • Patients must have received no more than one additional line of systemic therapy to treat lung cancer other than osimertinib (re-treatment with osimertinib after other systemic lung cancer therapy wil not count as a line of therapy). A line of therapy equals at least one month of treatment with discontinuation of therapy due to disease progression or intolerability. Osimertinib combined with chemotherapy or other targeted therapy wil count as one line of therapy. • Patients must be curently receiving osimertinib 80 mg for the treatment of metastatic disease or have evidence of metastatic disease recurence while receiving adjuvant osimertinib therapy. • Wiling to undergo pre-treatment research biopsy, if deemed safe by the investigator, or wiling to donate archived tissue from a biopsy performed within 60 days prior to the first dose of study drug. INCORPORATION BY REFERENCE

[0149] Al publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entireties to the same extent as if each individual publication, patent, or patent application was specificaly and individualy indicated to be incorporated by reference in its entirety. In case of conflict, the present application, including any definitions herein, wil control.

Claims

Client Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 CLAIMS We claim:

1. A method of treating lung cancer in a subject in need thereof, comprising administering to the subject on a 28-day dose schedule, a daily dose of osimertinib in combination with a twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof, wherein: the administered daily dose of osimertinib is from about 20 mg to about 240 mg and is administered on days 1-28 of the 28-day schedule; and the administered twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is from about 20 mg to about 50 mg and is administered on days 1-3, 8-10, and 15-17 of the 28-day schedule.

2. The method of claim 1, wherein the administration of alisertib is simultaneous with the administration of osimertinib.

3. The method of claim 1, wherein the administration of alisertib is successive with the administration of osimertinib.

4. The method of any of claims 1-3, wherein the subject has been treated previously with osimertinib and is resistant to osimertinib.

5. The method of any of claims 1-4, wherein the daily dose of osimertinib is from about 20 mg to about 100 mg.

6. The method of any of claims 1-5, wherein the daily dose of osimertinib is from about 40 mg to about 80 mg.

7. The method of any of claims 1-6, wherein the daily dose of osimertinib is about 80 mg.

8. The method of any of claims 1-7, wherein the twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is from about 30 mg to about 40 mg.

9. The method of any of claims 1-8, wherein the twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is about 30 mg.

10. The method of any of claims 1-9, wherein the twice-daily dose of alisertib or pharmaceuticaly acceptable salt thereof is about 40 mg.

11. The method of any of claims 1-10, wherein the lung cancer is epidermal growth factor receptor (EGFR) mutated lung cancer.

12. A method of treating lung cancer in a subject in need thereof, comprising:Client Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 administering to the subject on a 28-day dose schedule, a daily dose of osimertinib in combination with a twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof, wherein: the administered daily dose of osimertinib is from about 20 mg to about 240 mg and is administered on days 1-28 of the 28-day schedule; the administered twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is from about 20 mg to about 50 mg and is administered on days 1-3, 8-10, and 15-17 of the 28-day schedule; and the subject is determined not to contain one or more mutations in a p53 gene.

13. A method of treating lung cancer in a subject in need thereof, comprising: a. determining if a sample obtained from the subject contains one or more mutations in a p53 gene; b. selecting a subject having no mutations in the p53 gene based on the determination in step a); and c. administering to the subject selected in step b), a daily dose of osimertinib in combination with a twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof, wherein: the osimertinib and alisertib are administered on a 28-day schedule, the administered daily dose of osimertinib is from about 20 mg to about 240 mg and is administered on days 1-28 of the 28-day schedule; and the administered twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is from about 20 mg to about 50 mg and is administered on days 1-3, 8-10, and 15-17 of the 28-day schedule.

14. The method of claim 12 or claim 13, wherein the administration of alisertib is simultaneous with the administration of osimertinib.

15. The method of claim 12 or claim 13, wherein the administration of alisertib is successive with the administration of osimertinib.

16. The method of any of claims 12-15, wherein the daily dose of osimertinib is from about 20 mg to about 100 mg.

17. The method of any of claims 12-16, wherein the daily dose of osimertinib is from about 40 mg to about 80 mg.Client Ref No. SF2024-191 Atny Docket No. UCSF2- 43179.101 18. The method of any of claims 12-17, wherein the daily dose of osimertinib is about 80 mg.

19. The method of any of claims 12-18, wherein the twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is from about 30 mg to about 40 mg.

20. The method of any of claims 12-19, wherein the twice-daily dose of alisertib or a pharmaceuticaly acceptable salt thereof is about 30 mg.

21. The method of any of claims 12-20, wherein the twice-daily dose of alisertib or pharmaceuticaly acceptable salt thereof is about 40 mg.

22. The method of any of claims 12-21, wherein the lung cancer is epidermal growth factor receptor (EGFR) mutated lung cancer.

23. The method of any of claims 12-22, wherein the one or more mutations in the p53 gene is determined by a sequencing assay.

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