EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) TYROSINE KINASE INHIBITORS IN COMBINATION WITH AKT INHIBITORS FOR THE TREATMENT OF CANCER - Patent application

Abstract

The present specification relates to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for use in the treatment of cancer, wherein the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is administered in combination with an AKT inhibitor.

Description

[Technical field]

[0001] The present specification relates to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for use in the treatment of cancer (e.g., non-small cell lung cancer [NSCLC]), wherein the EGFR tyrosine kinase inhibitor (TKI) is administered in combination with an AKT inhibitor. [Background technology]

[0002] The discovery of activating mutations in epidermal growth factor receptor (EGFR) has revolutionized the treatment of the disease. In 2004, it was reported that activating mutations in exons 18-21 of EGFR correlate with the response of NSCLC to EGFR-TKI therapy (Non-Patent Document 1, Non-Patent Document 2). These mutations are estimated to occur in approximately 10-16% of human patients with NSCLC in the United States and Europe, and approximately 30-50% of human patients with NSCLC in Asia. The two most important EGFR activating mutations are exon 19 deletions and exon 21 missense mutations. Exon 19 deletions account for approximately 45% of known EGFR mutations. Eleven different mutations resulting in deletions of 3-7 amino acids have been detected in exon 19, all clustered around the uniformly deleted codons corresponding to amino acids 747-749. The most important exon 19 deletion is E746-A750. Missense mutations in exon 21 account for approximately 39 to 45% of known EGFR mutations, and among them, the substitution mutation L858R accounts for approximately 39% of all exon 21 mutations (Non-Patent Document 3).

[0003] Two first-generation (erlotinib and gefitinib), two second-generation (afatinib and dacomitinib) and one third-generation (osimertinib) epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are currently available for the management of EGFR mutation-positive NSCLC. All of these TKIs are effective in patients with NSCLC whose tumors harbor an in-frame deletion in exon 19 and an L858R point mutation in exon 21. These two mutations account for approximately 90% of all EGFR mutations. In approximately 50% of patients, resistance to first- and second-generation EGFR TKIs is mediated by the acquisition of the "gatekeeper" mutation, T790M. Currently, osimertinib is the only registered EGFR TKI that is active against exon 19 deletions and L858R mutations, independent of the presence of the T790M mutation. However, even patients treated with osimertinib eventually progress due to the development of acquired resistance, mainly due to other resistance mechanisms.Therefore, there remains a need to develop novel therapies for treating NSCLC, especially for patients whose disease has progressed after treatment with third-generation EGFR TKIs.

[0004] Induction of programmed cell death by apoptosis is a crucial mechanism of anticancer activity of osimertinib and other EGFR TKIs. However, certain cancers may develop (or be inherently) resistant to such apoptosis, reducing the effectiveness of treatment.

[0005] Through laboratory experiments with a population of cancer cells sensitive to osimertinib, it was found that the effect of EGFR TKIs could be enhanced in some patients by combined use with AKT inhibitors. AKT is a serine / threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration. Mammalian cells express three closely related AKT isoforms encoded by different genes: AKT1 (protein kinase Bα), AKT2 (protein kinase Bβ) and AKT3 (protein kinase Bγ). Exemplary AKT inhibitors include capivasertib or a pharma- ceutically acceptable salt thereof (also known as AZD5363, also known by the chemical name (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide), which is a selective inhibitor of all three AKT isoforms.

[0006] Without being bound by theory, it is proposed that in cancer cells that depend on the EGFR pathway, inhibiting this protein can induce a state in which cells are sensitive to AKT inhibitors. Cells that survive chronic treatment with EGFR TKI monotherapy may have defects in cell death and act as reservoirs for the development of clinical resistance. However, in a subset of these patients, the cellular adaptations that cancer cells require to avoid death in the presence of EGFR inhibition may reveal new vulnerabilities to AKT inhibitors.

[0007] In preclinical cell line models, a subpopulation of osimertinib-resistant cells showed enhanced sensitivity to AKT inhibitors compared with osimertinib-sensitive parental cells, suggesting that combining AKT with osimertinib may overcome emerging resistance and provide a potential avenue for treating patients whose cancers no longer respond to EGFR TKIs alone.

[0008] It was therefore determined that treatment with an AKT inhibitor could overcome such resistance and resensitize the cancer to the apoptotic effects of EGFR TKIs. Furthermore, a combination of an EGFR inhibitor and an AKT inhibitor could work together in therapy to prevent or delay the onset of resistance. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Science

[2004] ,vol.304,1497-1500 [Non-Patent Document 2] New England Journal of Medicine

[2004] , vol.350, 2129-2139 [Non-Patent Document 3] J. Thorac. Oncol.

[2010] , 1551-1558 Summary of the Invention [Means for solving the problem]

[0010] Provided herein is a means of utilizing AKT inhibitors in combination with EGFR TKIs to enhance the anti-proliferative and pro-apoptotic effects of EGFR TKI treatment in cancer (eg, NSCLC).

[0011] Thus, the present specification discloses the combination of an EGFR TKI with an AKT inhibitor for EGFR mutated NSCLC, both as a first-line treatment (i.e., in patients who have not been treated with an EGFR TKI) and as a treatment at the minimal residual disease stage (i.e., in patients who have been previously treated with an EGFR TKI, where the combination treatment is initiated at the time of maximum drug response when the number of residual tumor cells is so low that it does not cause any physical signs or symptoms).

[0012] In one aspect, there is provided an EGFR TKI for use in treating cancer in a human patient, administered in combination with an AKT inhibitor.

[0013] The terms "treat", "treating" and "treatment" refer to at least partially alleviating, inhibiting, preventing and / or reversing a condition, disorder or disease, such as lung cancer. The term "cancer treatment" includes both in vitro and in vivo treatments, including in warm-blooded animals, such as humans. The effectiveness of cancer treatments can be evaluated in a variety of ways, including, but not limited to, inhibition of cancer cell proliferation (including reversal of cancer growth), promotion of cancer cell death (e.g., by promoting apoptosis or another cell death mechanism), amelioration of symptoms, duration of response to treatment, delay of disease progression and prolongation of survival. Treatments can also be evaluated with respect to the nature and extent of side effects associated with treatment. Additionally, efficacy can be evaluated with respect to biomarkers, such as levels of expression or phosphorylation of proteins known to be associated with certain biological phenomena. Other evaluations of efficacy are known to those skilled in the art.

[0014] The phrase "in combination with" and similar terms (including "concurrently") encompasses the administration of two or more active pharmaceutical ingredients to a subject, including simultaneous administration of separate compositions, administration of separate compositions at different times, or administration of a composition in which two or more active pharmaceutical ingredients are present.

[0015] In a further aspect, there is provided the use of an EGFR TKI in the manufacture of a medicament for treating cancer in a human patient, wherein the EGFR TKI is administered in combination with an AKT inhibitor.

[0016] In a further aspect, a method of treating cancer in a human patient in need of such treatment is provided, comprising administering to the human patient a therapeutically effective amount of an EGFR TKI, wherein the EGFR TKI is administered in combination with a therapeutically effective amount of an AKT inhibitor.

[0017] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or combination of compounds described herein that is sufficient to achieve the intended use, including but not limited to disease treatment. Therapeutically effective amounts may vary depending on the intended use (in vitro or in vivo) or the subject and disease state to be treated (e.g., the subject's weight, age, and sex), the severity of the disease state, the method of administration, and the like, and can be readily determined by one of ordinary skill in the art. The term also applies to a dose that induces a particular response (e.g., the amount of apoptosis) in a target cell. The particular dose will vary depending on the particular compound selected, the administration regimen to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which the dose is administered, and the physical delivery system to which the compound is transported.

[0018] In a further aspect, there is provided a method of treating cancer in a human patient in need of such treatment, comprising administering to the human patient a first amount of an EGFR TKI and a second amount of an AKT inhibitor, wherein the first amount and the second amount together constitute a therapeutically effective amount.

[0019] In a further aspect, a pharmaceutical composition is provided comprising an EGFR TKI, an AKT inhibitor and a pharma- ceutically acceptable excipient.

[0020] The term "pharmaceutical acceptable" is used to specify that the subject (e.g., a salt, dosage form, or excipient (such as a diluent or carrier) is suitable for use in patients. Exemplary lists of pharmaceutical acceptable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use", P.H. Stahl and C.G. Wermuth, editors, Weinheim / Zurich: Wiley-VCH / VFiCA, 2002 or subsequent editions.

[0021] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine.

[0022] In a further aspect, there is provided an AKT inhibitor for use in treating cancer in a human patient, administered in combination with an EGFR TKI. [Brief description of the drawings]

[0023] [Figure 1] Viability assay (CTG) in PC9 PIK3CAH1047R and PC9 PIK3CAE453K cells compared to PC9 parental cells. PC9 PIK3CAm cells are more resistant to osimertinib (A). [Diagram 2] Viability assay (CTG) in PC9 PIK3CAH1047R cells compared to PC9 parental cells. PC9 PIK3CAm cells are more resistant to osimertinib and can be partially resensitized by co-treatment with 500 nM AZD5363. [Diagram 3]Viability assay (CTG) in PC9 PIK3CAE453K cells compared to PC9 parental cells. PC9 PIK3CAm cells are more resistant to osimertinib and can be partially resensitized by co-treatment with 500 nM AZD5363. [Figure 4] Osimertinib-mediated apoptotic response in PC9 PIK3CAH1047R cells compared to PC9 parental cells by caspase 3 / 7 activation assay. Reduced apoptotic response in PC9 PIK3CAH1047R that cannot be restored by co-treatment with AZD5363. [Diagram 5] Clonogenic assay in PC9 PIK3CAm compared to PC9 parental cells. PC9-PIK3Cam cells developed resistance to osimertinib that could be partially rescued by combination with capivasertib. [Figure 6] WB analysis in PC9 PIK3CAm cells treated with 160 nM osimertinib alone or in combination with capivasertib for 4 hours. [Figure 7] Cell viability (CTG) in two different HCC-827 PTENKO cell lines compared to parental cells. HCC-827 PTENKO cells are more resistant to osimertinib compared to parental cells. [Figure 8] Cell viability (CTG) in PC9 PTENKO cell lines untreated or exposed to osimertinib for 3 weeks compared to parental cells. PC9 PTENKO develops resistance after 3 weeks of drug selection. [Figure 9] Clonogenic assay in PC9 PTENKO cells treated with osimertinib 160 nM alone or in combination with AZD5363 500 nM for 3 or 5 weeks, respectively. PTENKO cells develop resistance that can be partially resensitized by combination with capivasertib. [Figure 10]Clonogenic assay in HCC-827 PTENKO cells treated with osimertinib 160 nM alone or in combination with AZD5363 500 nM for 3 or 5 weeks, respectively. PTENKO cells develop resistance that can be partially resensitized by combination with capivasertib. [Figure 11] Intracellular changes by WB analysis in HCC-827 PTENKO cell lines compared to the parental cell lines. [Figure 12] Intracellular changes by WB analysis in PC9 PTENKO (untreated or exposed to 160 nM osimertinib for 3 weeks) cell lines compared to parental cells. [Figure 13] Intracellular changes by WB analysis in HCC-827 PTENKO cell lines treated with capivasertib as monotherapy. [Figure 14] Intracellular changes by WB analysis in HCC-827 PTENKO cell lines treated with capivasertib in combination with osimertinib therapy. [Figure 15] Cell viability assay (CTG) in HCC-827 cells treated with osimertinib (3 nM-10 mM) alone or in combination with 500 nM capivasertib. [Figure 16] Clonogenic assays in two different PC9 PTENKO treated with osimertinib alone or in combination with capivasertib or a PI3K inhibitor compared to NTC parental cells (upper panel). PC9 PTENKO cells develop resistance to osimertinib, but can be partially resensitized by capivasertib. [Figure 17] Efficacy of combinations using EGFR TKI and AKT inhibitors in PC9 PIKC3AH1047 xenograft model. [Figure 18] Efficacy of combination using EGFR TKI and AKT inhibitor in PC9 PIKC3AE453K xenograft model. [Figure 19]Efficacy of combinations using EGFR TKI and AKT inhibitors in the LC-F-12 PIKC3AE545K xenograft model. [Figure 20] Efficacy of combinations using EGFR TKI and AKT inhibitors in the MR131 PTEND326H xenograft model. [Figure 21] CTG-2939 Efficacy of combination using EGFR TKI and AKT inhibitor in PTEN deep deletion xenograft model. [Figure 22] Efficacy of combinations using EGFR TKI and AKT inhibitors in the CTG-2180 PTENC304fs xenograft model. [Figure 23] Efficacy of combination using EGFR TKI and AKT inhibitor in PC9 PTENKO xenograft model. [Figure 24] Efficacy of combination using EGFR TKI and AKT inhibitor in HCC-827 PTENKO xenograft model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] EGFR mutation-positive NSCLC, patient selection and diagnostic methods In embodiments, the cancer is characterized by a PIK3CA mutation (e.g., a gain-of-function mutation or a deletion, substitution, or insertion mutation, such as a PIK3CA H1047R Mutations, PIKC3A E453K Mutations, PI3K E542K Mutation or PIKC3A E545K PI3KCA mutation status can be determined by methods known in the art.

[0025] In embodiments, the cancer is PTEN deficient (e.g., comprises cancerous cells (e.g., a population of cancerous cells, such as a majority of cancerous cells) with a reduced normal amount (e.g., compared to non-cancerous cells of the same patient) or reduced function of the PTEN tumor suppressor protein). PTEN status can be determined by methods known in the art.

[0026] In embodiments, the cancer is lung cancer, such as non-small cell lung cancer (NSCLC).

[0027] In embodiments, the NSCLC is EGFR mutation-positive NSCLC.

[0028] In an embodiment, the EGFR mutation-positive NSCLC comprises an activating mutation in EGFR. In a further embodiment, the EGFR mutation-positive NSCLC comprises a non-resistant mutation. In a further embodiment, the activating mutation in EGFR comprises an activating mutation in exons 18-21. In a further embodiment, the activating mutation in EGFR comprises a deletion of exon 19 or a missense mutation in exon 21. In a further embodiment, the activating mutation in EGFR comprises a deletion of exon 19 or a L858R substitution mutation. In a further embodiment, the mutation in EGFR comprises a T790M mutation.

[0029] In embodiments, the EGFR mutation-positive NSCLC is locally advanced EGFR mutation-positive NSCLC.

[0030] In embodiments, the EGFR mutation-positive NSCLC is metastatic EGFR mutation-positive NSCLC.

[0031] In embodiments, the EGFR mutation-positive NSCLC is unsuitable for either curative surgery or radiation therapy.

[0032] There are many methods for detecting activating mutations of EGFR, which are known to those skilled in the art. Several tests suitable for use in these methods have been approved by the US Food and Drug Administration (FDA). These methods include both tumor tissue-based and plasma-based diagnostic methods. In general, EGFR mutation status is first evaluated using tumor tissue biopsy samples from human patients. If tumor samples are not available or are negative, EGFR mutation status can be evaluated using plasma samples. A specific example of a diagnostic test suitable for detecting EGFR mutations, and in particular for detecting exon 19 deletions, L858R substitution mutations, and T790M mutations, is the Cobas™ EGFR Mutation Test v2 (Roche Molecular Diagnostics).

[0033] Thus, in an embodiment, the EGFR mutation-positive NSCLC comprises an activating mutation in EGFR (e.g., an activating mutation in exons 18-21, e.g., a deletion in exon 19, a missense mutation in exon 21, and a resistance mutation such as the L858R substitution mutation and the T790M mutation), and the EGFR mutation status of the human patient has been determined using a suitable diagnostic test. In a further embodiment, the EGFR mutation status has been determined using a tumor tissue sample. In a further embodiment, the EGFR mutation status has been determined using a plasma sample. In a further embodiment, the diagnostic method uses an FDA approved test. In a further embodiment, the diagnostic method uses the Cobas™ EGFR Mutation Test (v1 or v2).

[0034] In embodiments, the human patient is an EGFR TKI treatment naive human patient.

[0035] In an embodiment, the human patient has been previously treated with an EGFR TKI. In an embodiment, the human patient has been previously treated with osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient's disease has reached a maximal response (minimal residual disease) phase during or after a previous EGFR TKI treatment. In a further embodiment, the human patient's disease has reached a maximal response during or after a previous treatment with osimertinib or a pharmaceutically acceptable salt thereof. The EGFR TKI treatment includes treatment with either a first generation, second generation, or third generation EGFR TKI, or a combination thereof. In an embodiment, the human patient has EGFR T790M mutation-positive NSCLC.

[0036] EGFR TKI The EGFR TKI may be characterized as either a first, second or third generation EGFR TKI, as described below.

[0037] First-generation EGFR TKIs are reversible inhibitors of EGFR with activating mutations and do not inhibit EGFR with T790M mutations as well. Examples of first-generation TKIs include gefitinib and erlotinib.

[0038] Second-generation EGFR TKIs are irreversible inhibitors of EGFR with activating mutations and do not inhibit EGFR with T790M mutations as well. Examples of second-generation TKIs include afatinib and dacomitinib.

[0039] Third-generation EGFR TKIs are inhibitors of EGFR with activating mutations, and also significantly inhibit EGFR with the T790M mutation, but do not inhibit wild-type EGFR very well. Examples of third generation TKIs include the compound of formula (I), osimertinib, AZD3759 (zolifertinib), lazertinib, nazartinib (EGF816), CO1686 (rociletinib), HM61713 (olmutinib), ASP8273 (nacotinib), PF-06747775 (mavereltinib), avitinib (abivertinib), alflutinib (AST2818), CX-101 (orafeltinib, RX-518), aumoreltinib (HS-10296, almonertinib) and BPI-7711 (resivertinib).

[0040] In one aspect, the EGFR TKI is a first generation EGFR TKI. In a further embodiment, the first generation EGFR TKI is selected from the group consisting of gefitinib or a pharma- ceutically acceptable salt thereof, icotinib or a pharma- ceutically acceptable salt thereof, and erlotinib or a pharma- ceutically acceptable salt thereof.

[0041] In one embodiment, the EGFR TKI is a second generation EGFR TKI. In a further embodiment, the second generation EGFR TKI is selected from dacomitinib or a pharma- ceutically acceptable salt thereof and afatinib or a pharma- ceutically acceptable salt thereof.

[0042] In one embodiment, the EGFR TKI is a third generation EGFR TKI. In a further embodiment, the third generation EGFR TKI is a compound of formula (I) as defined below. In a further embodiment, the third generation EGFR TKI is selected from the group consisting of osimertinib or a pharmaceutically acceptable salt thereof, AZD3759 or a pharmaceutically acceptable salt thereof, lazertinib or a pharmaceutically acceptable salt thereof, abivertinib or a pharmaceutically acceptable salt thereof, alfurtinibe or a pharmaceutically acceptable salt thereof, CX-101 or a pharmaceutically acceptable salt thereof, HS-10296 or a pharmaceutically acceptable salt thereof, and BPI-7711 or a pharmaceutically acceptable salt thereof. In a further embodiment, the third generation EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof.

[0043] Compounds of formula (I) In one embodiment, the EGFR TKI has formula (I): [ka] (In the formula, G is selected from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, indol-3-yl, indazol-1-yl, 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-10-yl, 6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl, 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl, pyrrolo[3,2-b]pyridin-3-yl and pyrazolo[1,5-a]pyridin-3-yl; R 1 is selected from hydrogen, fluoro, chloro, methyl and cyano; R 2 is selected from methoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy and methyl; R 3are (3R)-3-(dimethylamino)pyrrolidin-1-yl, (3S)-3-(dimethyl-amino)pyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, [2-(dimethylamino)ethyl]-(methyl)amino, [2-(methylamino)ethyl](methyl)amino, 2-(dimethylamino)ethoxy, 2-(methylamino)ethoxy, 5-methyl-2,5-diazaspiro[3.4]oct-2-yl, (3aR,6aR)-5-methylhexa-hydro-pyrrolo[3,4- b] selected from pyrrol-1(2H)-yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperidin-1-yl, 4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl, methyl[2-(4-methylpiperazin-1-yl)ethyl]amino, methyl[2-(morpholin-4-yl)ethyl]amino, 1-amino-1,2,3,6-tetrahydropyridin-4-yl and 4-[(2S)-2-aminopropanoyl]piperazin-1-yl; R 4 is selected from hydrogen, 1-piperidinomethyl and N,N-dimethylaminomethyl; R 5 is independently selected from methyl, ethyl, propyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, and cyclopropyl; X is CH or N, and n is 0, 1 or 2. or a pharma- ceutically acceptable salt thereof.

[0044] In a further embodiment, the compound of formula (I) as defined above, wherein G is selected from indol-3-yl and indazol-1-yl, R 1 is selected from hydrogen, fluoro, chloro, methyl and cyano; R 2 is selected from methoxy and 2,2,2-trifluoroethoxy; R 3 is selected from [2-(dimethylamino)ethyl]-(methyl)amino, [2-(methylamino)ethyl](methyl)amino, 2-(dimethylamino)ethoxy and 2-(methylamino)ethoxy; R 4is hydrogen and R 5 is selected from methyl, 2,2,2-trifluoroethyl and cyclopropyl, X is CH or N, and n is 0 or 1, or a pharma- ceutically acceptable salt thereof.

[0045] Examples of compounds of formula (I) include those described in WO 2013 / 014448, WO 2015 / 175632, WO 2016 / 054987, WO 2016 / 015453, WO 2016 / 094821, WO 2016 / 070816 and WO 2016 / 173438.

[0046] Osimertinib and its pharmaceutical composition Osimertinib has the following chemical structure: [ka] has.

[0047] The free base of osimertinib is known by the chemical name N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide. Osimertinib is described in WO 2013 / 014448. Osimertinib is also known as AZD9291.

[0048] Osimertinib can be found in the form of mesylate: N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide mesylate. Osimertinib mesylate is also known as TAGRISSO™.

[0049] Osimertinib mesylate is currently approved for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC at a dose of 80 mg (expressed as the free base, equivalent to 95.4 mg osimertinib mesylate) in an oral once-daily tablet formulation. If dose modification is required, a 40 mg oral once-daily tablet formulation (expressed as the free base, equivalent to 47.7 mg osimertinib mesylate) is available. The tablet core includes pharmaceutical diluents (such as mannitol and microcrystalline cellulose), disintegrants (such as low-substituted hydroxypropylcellulose) and lubricants (such as sodium stearyl fumarate). Tablet formulations are described in WO 2015 / 101791.

[0050] Thus, in one embodiment, osimertinib or a pharma- ceutically acceptable salt thereof is in the form of a mesylate salt, i.e., N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide mesylate salt.

[0051] In one embodiment, osimertinib or a pharma- ceutically acceptable salt thereof is administered once daily. In a further embodiment, osimertinib mesylate is administered once daily.

[0052] In one embodiment, the total daily dose of osimertinib is about 80 mg. In a further embodiment, the total daily dose of osimertinib mesylate is about 95.4 mg.

[0053] In one embodiment, the total daily dose of osimertinib is about 40 mg. In a further embodiment, the total daily dose of osimertinib mesylate is about 47.7 mg.

[0054] In one embodiment, the osimertinib or a pharma- ceutically acceptable salt thereof is in tablet form.

[0055] In one embodiment, osimertinib or a pharma- ceutically acceptable salt thereof is administered in the form of a pharmaceutical composition comprising one or more pharma- ceutically acceptable excipients (e.g., diluents or carriers).In a further embodiment, the composition comprises one or more pharmaceutical diluents (such as mannitol and microcrystalline cellulose), one or more pharmaceutical disintegrants (such as low-substituted hydroxypropylcellulose), or one or more pharmaceutical lubricants (such as sodium stearyl fumarate).

[0056] In one embodiment, the composition is in the form of a tablet, wherein the tablet core comprises: (a) 2-70 parts of osimertinib or a pharma- ceutically acceptable salt thereof; (b) 5-96 parts of two or more pharmaceutical diluents; (c) 2-15 parts of one or more pharmaceutical disintegrants; and (d) 0.5-3 parts of one or more pharmaceutical lubricants, all parts being by weight and the sum of the parts being (a)+(b)+(c)+(d)=100.

[0057] In one embodiment, the composition is in the form of a tablet, wherein the tablet core comprises: (a) 7-25 parts osimertinib or a pharma- ceutically acceptable salt thereof; (b) 55-85 parts of two or more pharmaceutical diluents comprising microcrystalline cellulose and mannitol; (c) 2-8 parts of a pharmaceutical disintegrant comprising low-substituted hydroxypropylcellulose; and (d) 1.5-2.5 parts of a pharmaceutical lubricant comprising sodium stearyl fumarate, all parts being by weight and the sum of the parts being (a)+(b)+(c)+(d)=100.

[0058] In one embodiment, the composition is in the form of a tablet, wherein the tablet core comprises: (a) about 19 parts osimertinib mesylate, (b) about 59 parts mannitol, (c) about 15 parts microcrystalline cellulose, (d) about 5 parts low-substituted hydroxypropyl cellulose, and (e) about 2 parts sodium stearyl fumarate, all parts being by weight and the sum of the parts being (a)+(b)+(c)+(d)+(e)=100.

[0059] AZD3759 (zolifertinib) AZD3759 has the following chemical structure: [ka] has.

[0060] The free base of AZD3759 is known by the chemical name: 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxy-6-quinazolinyl(2R)-2,4-dimethyl-1-piperazinecarboxylate. AZD3759 is described in WO 2014 / 135876.

[0061] In one aspect, AZD3759 or a pharma- ceutically acceptable salt thereof is administered twice daily.In a further aspect, AZD3759 is administered twice daily.

[0062] In one embodiment, the total daily dose of AZD3759 is about 400 mg. In a further embodiment, about 200 mg of AZD3759 is administered twice daily.

[0063] Lazertinib Lazertinib has the following chemical structure: [ka] has.

[0064] The free base of lazertinib is known by the chemical name N-{5-[(4-{4-[(dimethylamino)methyl]-3-phenyl-1H-pyrazol-1-yl}-2-pyrimidinyl)amino]-4-methoxy-2-(4-morpholinyl)phenyl}acrylamide. Lazertinib is described in WO 2016 / 060443. Lazertinib is also known as YH25448 and GNS-1480.

[0065] In one embodiment, lazertinib or a pharma- ceutically acceptable salt thereof is administered once daily. In a further embodiment, lazertinib is administered once daily.

[0066] In one embodiment, the total daily dose of lazertinib is about 20 to 320 mg.

[0067] In one embodiment, the total daily dose of lazertinib is about 240 mg.

[0068] Avitinib Avitinib has the following chemical structure: [ka] has.

[0069] The free base of Avitinib is known by the chemical name: N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo(2,3-d)pyrimidin-4-yl)oxy)phenyl)prop-2-enamide. Avitinib is disclosed in US Patent Publication No. 2014038940. Avitinib is also known as abivertinib.

[0070] In one embodiment, avitinib or a pharma- ceutically acceptable salt thereof is administered twice daily. In a further embodiment, avitinib maleate is administered twice daily.

[0071] In one embodiment, the total daily dose of avitinib maleate is about 600 mg.

[0072] Alfutinib Alflutinib has the following chemical structure: [ka] has.

[0073] Alflutinib free base is known by the chemical name N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide. Alflutinib is disclosed in WO 2016 / 15453. Alflutinib is also known as AST2818.

[0074] In one embodiment, alfutinib or a pharma- ceutically acceptable salt thereof is administered once daily.In a further embodiment, alfutinib mesylate is administered once daily.

[0075] In one embodiment, the total daily dose of alfutinib mesylate is about 80 mg.

[0076] In one embodiment, the total daily dose of alfutinib mesylate is about 40 mg.

[0077] Afatinib Afatinib has the following chemical structure: [ka] has.

[0078] Afatinib free base is known by the chemical name: N-[4-(3-chloro-4-fluoroanilino)-7-[(3S)-oxolan-3-yl]oxyquinazolin-6-yl]-4-(dimethylamino)but-2-enamide. Afatinib is disclosed in WO 02 / 50043. Afatinib is also known as Gilotrif.

[0079] In one embodiment, afatinib or a pharma- ceutically acceptable salt thereof is administered once daily. In a further embodiment, afatinib dimaleate is administered once daily.

[0080] In one embodiment, the total daily dose of afatinib dimaleate is about 40 mg.

[0081] In one embodiment, the total daily dose of afatinib dimaleate is about 30 mg.

[0082] CX-101 CX-101 has the following chemical structure: [ka] has.

[0083] The free base of CX-101 is known by the chemical name: N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide. CX-101 is disclosed in WO 2015 / 027222. CX-101 is also known as RX-518 and orafertinib.

[0084] HS-10296 (almonertinib, aumoretinib) HS-10296 (almonertinib, aumoretinib) has the following chemical structure: [ka] has.

[0085] The free base of HS-10296 is known by the chemical name: N-[5-[[4-(1-cyclopropylindol-3-yl)pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-phenyl]prop-2-enamide. HS-10296 is disclosed in WO 2016 / 054987.

[0086] In one embodiment, the total daily dose of HS-10296 is about 110 mg.

[0087] BPI-7711 (resivertinib) BPI-7711 has the following chemical structure: [ka] has.

[0088] The free base of BPI-7711 is known by the chemical name: N-[2-[2-(dimethylamino)ethoxy]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide. BPI-7711 is disclosed in WO 2016 / 94821.

[0089] In one embodiment, the total daily dose of BPI-7711 is about 180 mg.

[0090] Dacomitinib Dacomitinib has the following chemical structure: [ka] has.

[0091] The free form of dacomitinib is known by the chemical name: (2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-4-(piperidin-1-yl)but-2-enamide. Dacomitinib is described in WO 2005 / 107758. Dacomitinib is also known as PF-00299804.

[0092] Dacomitinib can be found in the form of dacomitinib monohydrate, i.e. (2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-4-(piperidin-1-yl)but-2-enamide monohydrate.

[0093] In one embodiment, dacomitinib or a pharma- ceutically acceptable salt thereof is administered once daily. In a further embodiment, dacomitinib monohydrate is administered once daily.

[0094] In one embodiment, the total daily dose of dacomitinib monohydrate is about 45 mg.

[0095] In one embodiment, the dacomitinib or a pharma- ceutically acceptable salt thereof is in tablet form.

[0096] In one embodiment, dacomitinib or a pharma- ceutically acceptable salt thereof is administered in the form of a pharmaceutical composition comprising one or more pharma- ceutically acceptable excipients. In a further embodiment, the one or more pharma- ceutically acceptable excipients comprise lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.

[0097] Icotinib Icotinib has the following chemical structure: [ka] has.

[0098] Icotinib free base has the chemical name: N-(3-ethynylphenyl)-2,5,8,11-tetraoxa-15,17-diazatricyclo[10.8.0.0 14,19 ]Icotinib is known as Icosa-1(12),13,15,17,19-pentaen-18-amine. Icotinib is disclosed in WO2013064128. Icotinib is also known by the alias Conmana.

[0099] In an embodiment, Icotinib or a pharma- ceutically acceptable salt thereof is administered three times per day.In a further embodiment, Icotinib hydrochloride is administered three times per day.

[0100] In an embodiment, the total daily dose of icotinib hydrochloride is about 375 mg.

[0101] Gefitinib Gefitinib has the following chemical structure: [ka] has.

[0102] Gefitinib free base is known by the chemical name: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine. Gefitinib is disclosed in WO 1996 / 033980. Gefitinib is also known as IRESSA®.

[0103] In an embodiment, gefitinib or a pharma- ceutically acceptable salt thereof is administered once daily.In a further embodiment, gefitinib is administered once daily.

[0104] In embodiments, the total daily dose of gefitinib is about 250 mg.

[0105] Erlotinib Erlotinib has the following chemical structure: [ka] has.

[0106] The free base of erlotinib is known by the chemical name: N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine. Erlotinib is disclosed in WO 1996 / 030347. Erlotinib is also known as TARCEVA.

[0107] In an embodiment, erlotinib or a pharma- ceutically acceptable salt thereof is administered once daily.In a further embodiment, erlotinib is administered once daily.

[0108] In embodiments, the total daily dose of erlotinib is about 150 mg.

[0109] In embodiments, the total daily dose of erlotinib is about 100 mg.

[0110] AKT inhibitors In embodiments, an AKT inhibitor is any molecule that binds to and inhibits the activity of one or more AKT isoforms.

[0111] In embodiments, the AKT inhibitor is milansertib (ARQ-092) or a pharma- ceutically acceptable salt thereof, BAY1125976 or a pharma- ceutically acceptable salt thereof, borsertib or a pharma- ceutically acceptable salt thereof, AT7867 or a pharma- ceutically acceptable salt thereof, CCT128930 or a pharma- ceutically acceptable salt thereof, A-674563 or a pharma- ceutically acceptable salt thereof, PHT-427 or a pharma- ceutically acceptable salt thereof, Akti-1 / 2 or a pharma- ceutically acceptable salt thereof, AT13148 or a pharma- ceutically acceptable salt thereof, SC79 or a pharma- ceutically acceptable salt thereof, capivasertib or a pharma- ceutically acceptable salt thereof, miltefosine or a pharma- ceutical and ipatasertib (GDC-0068) or a pharmaceutically acceptable salt thereof.

[0112] In embodiments, the AKT inhibitor is selected from the group consisting of capivasertib or a pharma- ceutically acceptable salt thereof, perifosine or a pharma- ceutically acceptable salt thereof, MK-2206 or a pharma- ceutically acceptable salt thereof, RX-0201 or a pharma- ceutically acceptable salt thereof, erucylphosphocholine or a pharma- ceutically acceptable salt thereof, PBI-05204 or a pharma- ceutically acceptable salt thereof, GSK690693 or a pharma- ceutically acceptable salt thereof, uplosertib (GSK2141795) or a pharma- ceutically acceptable salt thereof, XL-418 or a pharma- ceutically acceptable salt thereof, and ipatasertib or a pharma- ceutically acceptable salt thereof.

[0113] In embodiments, the AKT inhibitor is selected from the group consisting of capivasertib or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, afuresertib (GSK2110183) or a pharmaceutically acceptable salt thereof, uplosertib (GSK2141795) or a pharmaceutically acceptable salt thereof, and ipatasertib (GDC-0068) or a pharmaceutically acceptable salt thereof.

[0114] Capivasertib Capivasertib has the following chemical structure: [ka] has.

[0115] The free base of capivasertib is known by the chemical name: (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide). Capivasertib is disclosed in WO 2009 / 047563, which discloses capivasertib (in Example 9) and describes its synthesis.

[0116] In one embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered in the form of a pharmaceutical composition comprising one or more pharma- ceutically acceptable excipients. In a further embodiment, the composition comprises one or more pharmaceutical diluents (such as mannitol and microcrystalline cellulose), one or more pharmaceutical disintegrants (such as low-substituted hydroxypropylcellulose), or one or more pharmaceutical lubricants (such as sodium stearyl fumarate).

[0117] In one embodiment, the composition is in the form of a tablet.

[0118] In combination with osimertinib, capivasertib, or a pharma- ceutically acceptable salt thereof, is generally administered to a subject at a daily dosage of about 100 mg to about 1600 mg.

[0119] In some embodiments, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 150 mg to about 1500 mg. In one aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 200 mg to about 1400 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 300 mg to about 1300 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 400 mg to about 1200 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 500 mg to about 1100 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 600 mg to about 1000 mg. In some embodiments, capivasertib, or a pharma- ceutically acceptable salt thereof, is administered to a subject once daily (QD).

[0120] In one embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily at a dose of about 100 mg to about 1000 mg.

[0121] In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily at a dose of about 150 mg to about 900 mg. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily at a dose of about 200 mg to about 850 mg. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily at a dose of about 250 mg to about 800 mg. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily at a dose of about 300 mg to about 750 mg.

[0122] In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily at a dose of about 350 mg to about 700 mg.In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily at a dose of about 400 mg to about 650 mg.

[0123] In some embodiments, capivasertib or a pharma- ceutically acceptable salt thereof is administered to a subject twice daily (BID). In one aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 50 mg to about 900 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 100 mg to about 875 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg to about 850 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 250 mg to about 825 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 150 mg to about 250 mg. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 250 mg to about 350 mg. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 350 mg to about 450 mg. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 450 mg to about 550 mg. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 550 mg to about 650 mg. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 650 mg to about 750 mg. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 750 mg to about 850 mg twice daily. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 160 mg twice daily. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 200 mg twice daily. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 240 mg twice daily. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 280 mg twice daily. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 320 mg twice daily. In another embodiment, capivasertib, or a pharma- ceutically acceptable salt thereof, is administered at a dosage of about 360 mg twice daily.In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 400 mg twice daily. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 440 mg twice daily. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 480 mg twice daily. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 520 mg twice daily. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 560 mg twice daily. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 600 mg twice daily. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 640 mg twice daily. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 680 mg twice daily. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 720 mg twice daily. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 760 mg twice daily. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 800 mg twice daily.

[0124] In some embodiments, capivasertib or a pharmaceutically acceptable salt thereof is administered under a continuous dosing schedule. In one aspect, for example, capivasertib or a pharmaceutically acceptable salt thereof is administered for more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, more than 14 days, more than 21 days, more than 28 days, more than 35 days, more than 42 days, more than 49 days, or more than 56 days. In another aspect, the dosing cycle is 28 days. The administration of capivasertib or a pharmaceutically acceptable salt thereof and the repetition of the dosing cycle can be continued as long as it is tolerated and beneficial to the subject.

[0125] In some embodiments, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily (QD) under a continuous dosing schedule. In one aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily under a continuous dosing schedule at a dose of about 100 mg to about 900 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily under a continuous dosing schedule at a dose of about 150 mg to about 875 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily under a continuous dosing schedule at a dose of about 175 mg to about 850 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily under a continuous dosing schedule at a dose of about 200 mg to about 825 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily under a continuous dosing schedule at a dose of about 225 mg to about 800 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily under a continuous dosing schedule at a dose of about 250 mg to about 750 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily under a continuous dosing schedule at a dose of about 275 mg to about 700 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily under a continuous dosing schedule at a dose of about 300 mg to about 650 mg. In some embodiments, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily (BID) under a continuous dosing schedule. In one embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 100 mg to about 800 mg under a continuous dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 150 mg to about 750 mg under a continuous dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg to about 700 mg under a continuous dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 225 mg to about 650 mg under a continuous dosing schedule.In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 250 mg to about 650 mg under a continuous administration schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 300 mg to about 600 mg under a continuous administration schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg to about 300 mg under a continuous administration schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 300 mg to about 400 mg under a continuous administration schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 400 mg to about 500 mg under a continuous administration schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 500 mg to about 600 mg under a continuous dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 600 mg to about 700 mg under a continuous dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 700 mg to about 800 mg under a continuous dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 160 mg under a continuous dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg under a continuous dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 240 mg twice daily under a continuous dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 280 mg twice daily under a continuous dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 320 mg twice daily under a continuous dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 360 mg twice daily under a continuous dosing schedule.In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 400 mg twice daily under a sequential dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 440 mg twice daily under a sequential dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 480 mg twice daily under a sequential dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 520 mg twice daily under a sequential dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 580 mg twice daily under a sequential dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 600 mg twice daily under a sequential dosing schedule. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 640 mg twice daily under a continuous dosing schedule. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 680 mg twice daily under a continuous dosing schedule. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 720 mg twice daily under a continuous dosing schedule. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 760 mg twice daily under a continuous dosing schedule. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 800 mg twice daily under a continuous dosing schedule. In some embodiments, capivasertib or a pharma- ceutically acceptable salt thereof is administered to a subject on an intermittent dosing schedule. Administration of capivasertib or a pharma- ceutically acceptable salt thereof on an intermittent dosing schedule can, for example, provide increased efficacy and / or tolerability over a continuous dosing schedule. In one embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered intermittently on a 1 day on / 6 days off schedule (i.e., capivasertib or a pharma- ceutically acceptable salt thereof is administered on one day, followed by 6 days off).In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered intermittently on a 2 days on / 5 days off schedule (i.e., capivasertib or a pharma- ceutically acceptable salt thereof is administered for 2 days followed by a 5 day rest day). In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered intermittently on a 3 days on / 4 days off schedule (i.e., capivasertib or a pharma- ceutically acceptable salt thereof is administered for 3 days followed by a 4 day rest day). In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered intermittently on a 4 days on / 3 days off schedule (i.e., capivasertib or a pharma- ceutically acceptable salt thereof is administered for 4 days followed by a 3 day rest day). In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered intermittently on a 5 day on / 2 day off schedule (i.e., capivasertib or a pharma- ceutically acceptable salt thereof is administered for 5 days followed by a 2 day off day). In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered intermittently on a 6 day on / 1 day off schedule (i.e., capivasertib or a pharma- ceutically acceptable salt thereof is administered for 6 days followed by a 1 day off day). The dosing cycle of such an embodiment would then be repeated as long as tolerated and beneficial to the subject. In some embodiments, the dosing cycle is 7 days. In one aspect, the dosing cycle is 14 days. In another aspect, the dosing cycle is 21 days. In another aspect, the dosing cycle is 28 days. In another aspect, the dosing cycle is 2 months. In another aspect, the dosing cycle is 6 months. In another embodiment, the administration cycle is one year.

[0126] In some embodiments, the dosing cycle is 28 days, but capivasertib or a pharma- ceutically acceptable salt thereof is not co-administered to the subject during the fourth week of the dosing cycle (i.e., there is a drug holiday of capivasertib or a pharma- ceutically acceptable salt thereof during the final week of the dosing cycle).

[0127] In some embodiments, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily (QD) under an intermittent dosing schedule. In one aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily under an intermittent dosing schedule at a dose of about 100 mg to about 900 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily under an intermittent dosing schedule at a dose of about 150 mg to about 850 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily under an intermittent dosing schedule at a dose of about 175 mg to about 800 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily under an intermittent dosing schedule at a dose of about 200 mg to about 750 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily under an intermittent dosing schedule at a dose of about 225 mg to about 725 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily under an intermittent dosing schedule at a dose of about 250 mg to about 700 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily under an intermittent dosing schedule at a dose of about 275 mg to about 675 mg. In another aspect, capivasertib or a pharma- ceutically acceptable salt thereof is administered once daily under an intermittent dosing schedule at a dose of about 300 mg to about 650 mg. In some embodiments, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily (BID) under an intermittent dosing schedule. In one embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 100 mg to about 800 mg under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 150 mg to about 750 mg under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg to about 700 mg under an intermittent dosing schedule.In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 225 mg to about 675 mg under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 250 mg to about 650 mg under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 300 mg to about 625 mg under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg to about 300 mg under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 300 mg to about 400 mg under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 400 mg to about 500 mg under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 500 mg to about 600 mg under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 600 mg to about 700 mg under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 700 mg to about 800 mg under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered twice daily at a dose of about 160 mg under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 200 mg twice daily under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 240 mg twice daily under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 280 mg twice daily under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 320 mg twice daily under an intermittent dosing schedule.In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 360 mg twice daily under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 400 mg twice daily under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 440 mg twice daily under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 480 mg twice daily under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 520 mg twice daily under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 580 mg twice daily under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 600 mg twice daily under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 640 mg twice daily under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 680 mg twice daily under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 720 mg twice daily under an intermittent dosing schedule. In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 760 mg twice daily under an intermittent dosing schedule.In another embodiment, capivasertib or a pharma- ceutically acceptable salt thereof is administered at a dose of about 800 mg twice daily under an intermittent dosing schedule.

[0128] Perifosine Perifosine has the following chemical structure: [ka] has.

[0129] Perifosine is known by the chemical name 1,1-dimethylpiperidinium-4-yl octadecyl phosphate. Perifosine is disclosed in U.S. Patent No. 8,383,607.

[0130] MK-2206 MK-2206 has the following chemical structure: [ka] has.

[0131] The free base of MK-2206 is known by the chemical name: 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3(2H)-one. MK-2206 is disclosed in WO2008070016.

[0132] GSK690693 GSK690693 has the following chemical structure: [ka] has.

[0133] The free base of GSK690693 is known by the chemical name: 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol. GSK690693 is disclosed in WO2007058850.

[0134] Afuresertib Afuresertib (GSK2110183) has the following chemical structure: [ka] has.

[0135] The free base of afuresertib is known by the chemical name: N-[(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide. Afuresertib is disclosed in WO2008098104.

[0136] Euprosertib Yuplosertib (GSK2141795) has the following chemical structure: [ka] has.

[0137] The free base of uprosertib is known by the chemical name: N-[(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide. Yuplosertib is disclosed in WO2008098104.

[0138] Ipatasertib Ipatasertib has the following chemical structure: [ka] has.

[0139] The free base of ipatasertib is known by the chemical name: 2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one. Ipatasertib is disclosed in WO2008006040.

[0140] Further embodiments In one aspect, EGFR TKI is provided for use in treating cancer in human patients, which is administered in combination with AKT inhibitor.In an embodiment, cancer is lung cancer, such as NSCLC.In another further embodiment, NSCLC is EGFR mutation-positive NSCLC.

[0141] In one aspect, a method is provided for treating cancer in a human patient in need of such treatment, comprising administering to the human patient a therapeutically effective amount of EGFR TKI, wherein the EGFR TKI is administered in combination with a therapeutically effective amount of an AKT inhibitor.In an embodiment, the cancer is lung cancer, such as NSCLC.In another further embodiment, the NSCLC is EGFR mutation-positive NSCLC.

[0142] In one aspect, a method of treating cancer is provided in a human patient in need of such treatment, comprising administering to the human patient a first amount of an EGFR TKI and a second amount of an AKT inhibitor, the first amount and the second amount together constituting a therapeutically effective amount.In an embodiment, the cancer is lung cancer, such as NSCLC.In another further embodiment, the NSCLC is EGFR mutation-positive NSCLC.

[0143] In one aspect, the use of EGFR TKI is provided in the manufacture of a medicament for treating cancer in a human patient, wherein the EGFR TKI is administered in combination with an AKT inhibitor.In an embodiment, the cancer is lung cancer, such as NSCLC.In another further embodiment, the NSCLC is EGFR mutation-positive NSCLC.

[0144] In one aspect, a combination of an EGFR TKI and an AKT inhibitor is provided for use in treating cancer in a human patient. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is a human patient who has not been treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with osimertinib or a pharmaceutically acceptable salt thereof. In another further embodiment, the cancer is a lung cancer, such as NSCLC. In another further embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0145] In one aspect, a method of treating cancer in a human patient in need of such treatment is provided, comprising administering to the human patient a combination of a therapeutically effective amount of an EGFR TKI and a therapeutically effective amount of an AKT inhibitor. In an embodiment, the EGFR TKI is osimertinib or a pharma- ceutically acceptable salt thereof. In a further embodiment, the human patient is a human patient who has not been treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with osimertinib or a pharma- ceutically acceptable salt thereof. In another further embodiment, the cancer is a lung cancer, such as NSCLC. In another further embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0146] In one aspect, a method of treating cancer in a human patient in need of such treatment is provided, comprising administering to the human patient a first amount of an EGFR TKI and a second amount of an AKT inhibitor, the first amount and the second amount together constituting a therapeutically effective amount. In an embodiment, the EGFR TKI is osimertinib or a pharma- ceutically acceptable salt thereof. In a further embodiment, the human patient is a human patient who has not been treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with osimertinib or a pharma- ceutically acceptable salt thereof. In another further embodiment, the cancer is a lung cancer, such as NSCLC. In another further embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0147] In one aspect, there is provided a use of a combination of an EGFR TKI and an AKT inhibitor in the manufacture of a medicament for treating cancer in a human patient. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is a human patient who has not been treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with osimertinib or a pharmaceutically acceptable salt thereof. In another further embodiment, the cancer is a lung cancer, such as NSCLC. In another further embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0148] In one aspect, a combination of osimertinib or a pharma- ceutically acceptable salt thereof and an AKT inhibitor is provided for use in treating cancer in a human patient, wherein osimertinib or a pharma- ceutically acceptable salt thereof is administered to the human patient before the AKT inhibitor is administered to the human patient. In an embodiment, the cancer is lung cancer, such as NSCLC. In another further embodiment, the NSCLC is EGFR mutation-positive NSCLC.

[0149] In one aspect, a method of treating cancer in a human patient in need of such treatment is provided, comprising administering to the human patient a combination of a therapeutically effective amount of osimertinib or a pharma- ceutically acceptable salt thereof and a therapeutically effective amount of an AKT inhibitor, wherein the osimertinib or a pharma- ceutically acceptable salt thereof is administered to the human patient before the AKT inhibitor is administered to the human patient. In an embodiment, the cancer is lung cancer, such as NSCLC. In another further embodiment, the NSCLC is EGFR mutation-positive NSCLC.

[0150] In one aspect, a method of treating cancer in a human patient in need of such treatment is provided, comprising administering to the human patient a first amount of an EGFR TKI and a second amount of an AKT inhibitor, the first amount and the second amount together constituting a therapeutically effective amount, and osimertinib or a pharma- ceutically acceptable salt thereof is administered to the human patient before the AKT inhibitor is administered to the human patient. In an embodiment, the cancer is lung cancer, such as NSCLC. In another further embodiment, the NSCLC is EGFR mutation-positive NSCLC.

[0151] In one aspect, there is provided a use of osimertinib or a pharma- ceutically acceptable salt thereof in combination with an AKT inhibitor for the manufacture of a medicament for treating cancer in a human patient, wherein osimertinib or a pharma- ceutically acceptable salt thereof is administered to the human patient before the AKT inhibitor is administered to the human patient. In an embodiment, the cancer is lung cancer, such as NSCLC. In another further embodiment, the NSCLC is EGFR mutation-positive NSCLC.

[0152] In one aspect, an EGFR TKI is provided for use in treating cancer in a human patient, the treatment comprising administering to the human patient i) an EGFR TKI, and ii) an AKT inhibitor, separately, sequentially or simultaneously. When the treatment is separate or sequential, the interval between administration of the EGFR TKI and the AKT inhibitor can be selected to ensure a combined therapeutic effect.

[0153] A "therapeutic effect" includes a therapeutic benefit and / or a prophylactic benefit. A prophylactic benefit includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting or reversing the progression of a disease or condition, or any combination thereof.

[0154] In embodiments, the administration of the EGFR TKI and the AKT inhibitor is sequential, with the EGFR TKI being administered before the AKT inhibitor.

[0155] In an embodiment, the EGFR TKI is osimertinib or a pharma- ceutically acceptable salt thereof. In a further embodiment, the human patient is a human patient who has not been treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with osimertinib or a pharma- ceutically acceptable salt thereof. In another further embodiment, the cancer is a lung cancer, such as NSCLC. In another further embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0156] In one aspect, a method of treating cancer in a human patient in need of such treatment is provided, comprising administering to the human patient i) a therapeutically effective amount of an EGFR TKI, and ii) a therapeutically effective amount of an AKT inhibitor, either separately, sequentially or simultaneously. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is a human patient who has not been treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with osimertinib or a pharmaceutically acceptable salt thereof. In another further embodiment, the cancer is a lung cancer, such as NSCLC. In another further embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0157] In one aspect, a method of treating cancer in a human patient in need of such treatment is provided, comprising administering to the human patient, separately, sequentially or simultaneously, i) a first amount of an EGFR TKI, and ii) a second amount of an AKT inhibitor, the first amount and the second amount together constituting a therapeutically effective amount. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is a human patient who has not been treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with osimertinib or a pharmaceutically acceptable salt thereof. In another further embodiment, the cancer is a lung cancer, such as NSCLC. In another further embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0158] In one aspect, there is provided a use of an EGFR TKI in the manufacture of a medicament for treating cancer in a human patient, the treatment comprising administering to the human patient i) an EGFR TKI and ii) an AKT inhibitor separately, sequentially or simultaneously. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is a human patient who has not been treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with osimertinib or a pharmaceutically acceptable salt thereof. In another further embodiment, the cancer is a lung cancer, such as NSCLC. In another further embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0159] In one aspect, there is provided an AKT inhibitor for use in treating cancer in a human patient, administered in combination with an EGFR TKI.

[0160] In one aspect, an AKT inhibitor is provided for use in treating cancer in a human patient, the treatment comprising administering to the human patient i) an AKT inhibitor and ii) an EGFR TKI, either separately, sequentially or simultaneously. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is a human patient who has not been treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with osimertinib or a pharmaceutically acceptable salt thereof. In another further embodiment, the cancer is a lung cancer, such as NSCLC. In another further embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0161] In one aspect, there is provided a use of an AKT inhibitor in the manufacture of a medicament for treating cancer in a human patient, the treatment comprising administering to the human patient i) an EGFR TKI and ii) an AKT inhibitor separately, sequentially or simultaneously. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is a human patient who has not been treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with an EGFR TKI. In a further embodiment, the human patient has been previously treated with osimertinib or a pharmaceutically acceptable salt thereof. In another further embodiment, the cancer is a lung cancer, such as NSCLC. In another further embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0162] In one aspect, - a first pharmaceutical composition comprising an EGFR TKI and a pharma- ceutical acceptable excipient; - a second pharmaceutical composition comprising an AKT inhibitor and a pharma- ceutically acceptable excipient; A kit is provided comprising:

[0163] In one aspect, an AKT inhibitor is provided for use in treating non-small cell lung cancer in a human patient, wherein the patient's disease has reached a maximal response during or after a previous EGFR TKI treatment. In an embodiment, the human patient's disease has progressed during or after a previous treatment with osimertinib or a pharma- ceutically acceptable salt thereof.

[0164] In one aspect, there is provided osimertinib, or a pharma- ceutically acceptable salt thereof, in the treatment of non-small cell lung cancer in a human patient, wherein the human patient's disease has progressed during or after prior treatment with a different EGFR TKI.

[0165] In one aspect, a method of treating non-small cell lung cancer in a human patient in need of such treatment is provided, comprising administering to the human patient a therapeutically effective amount of an AKT inhibitor, wherein the patient's disease has progressed during or after prior EGFR TKI treatment. In an embodiment, the human patient's disease has progressed during or after prior treatment with osimertinib or a pharma- ceutically acceptable salt thereof.

[0166] In one aspect, there is provided the use of an AKT inhibitor in the manufacture of a medicament for the treatment of non-small cell lung cancer in a human patient, wherein the patient's disease has progressed during or after prior EGFR TKI treatment. In an embodiment, the human patient's disease has progressed during or after prior treatment with osimertinib or a pharma- ceutically acceptable salt thereof. EXAMPLES

[0167] The following specific examples are provided for illustrative purposes only with reference to the accompanying drawings and are not to be construed as limiting the teachings herein.

[0168] PC9 is a cell line derived from human lung adenocarcinoma with activating mutations in EGFR del E746_A750 (Ex19-del). HCC-827 is a cell line derived from human lung adenocarcinoma with activating mutations in EGFR E746-A750 (Ex19del). Both cell lines were obtained from ATCC. LC-F-12 is a cell line derived from human lung adenocarcinoma with activating point mutations in EGFR L858R and PIKC3A E545K, and was obtained from Xentech. MR131 is an in-house PDX derived from human lung adenocarcinoma with activating point mutations in EGFR L858R and PTEN D326H. CTG-2939 is a PDX derived from human lung adenocarcinoma with activating mutations in EGFR E746-A750 (Ex19del) and deep deletion of PTEN. CTG-2180 is a PDX derived from a human lung adenocarcinoma harboring an activating mutation at EGFR L747_T751del (Ex19del) and a PTEN frameshift at C304, both models are available from Champions Oncology.

[0169] Unless otherwise stated, all reagents were commercially available and were used as supplied.

[0170] Example 1: Activating mutations in PIK3CA promote resistance to osimertinib in vitro, which can be overcome by combination treatment with capivasertib. To preclinically test the hypothesis that activating mutations in PIK3CA promote resistance to osimertinib, we used CRISPR / Cas9 technology to transfect lung cancer cell line models with PIK3CA H1047R and PIK3CA E453KEach variant of PIK3CA was introduced into the PIK3CA-positive cells. Because the efficiency of knock-in using this technology is usually low, only a small proportion of cells were genetically modified, which was expected to mimic the emergence of simultaneous resistance mutations in tumors. This heterogeneous cell pool was then cultured under the selective pressure of osimertinib (100 nM) for 3 weeks to generate a cell pool resistant to osimertinib for downstream analysis. DNA sequencing (NGS and Sanger) of the final CRISPR cell pool of osimertinib selection confirmed the selective growth of PIK3CA H1047R-positive and PIK3CA E453K-positive cells, indicating that the inserted PIK3CA mutations conferred resistance to osimertinib.

[0171] PIK3CAm-induced resistance to osimertinib and its rescue by combination with capivasertib were analyzed in more detail by various experimental approaches, including the following:

[0172] a) Cell viability: The viability of osimertinib-resistant PC9-PIK3CAm cell pools was compared to parental PC9 cells when treated with osimertinib alone or in combination with capivasertib. PIK3CAm-induced resistance to osimertinib was determined by the EC 50 This was associated with an increase in PIK3CA expression, which could be partially rescued by co-treatment with capivasertib (Figures 1-3: PC9-PIK3CA treated with osimertinib 3 nM-10 μM alone or in combination with capivasertib 500 nM for 6 days). H1047R and PC9-PIK3CA E453K Cell-TiterGlo® assay in .

[0173] b) Caspase 3 / 7 activation assay: The osimertinib-induced apoptotic response in PC9-PIK3CAm cells was compared to PC9 parental cells by the Caspase-Glo® 3 / 7 assay, a luminescent assay that measures intracellular caspase-3 and caspase-7 activity. PIK3CAm-induced resistance to osimertinib was associated with a reduced apoptotic response that could not be restored by co-treatment with capivasertib (Figure 4).

[0174] c) Clonogenic assay: The proliferation of PC9-PIK3CAm cells was compared to parental PC9. Cells were cultured at low density (1.5 × 10 3 ) into 6-well plates and treated with osimertinib (160 nM) alone or in combination with capivasertib (500 nM). At the end of treatment (day 8), cells were stained with crystal violet and cell density (% surface) was quantified by ImageJ. As shown in Figure 5, PC9-PIK3Cam cells developed resistance to osimertinib, which could be partially rescued by combination with capivasertib.

[0175] d) Intracellular changes by WB analysis. Protein analysis by Western blot showed increased basal levels of pAKT, pERK and pS6 in PC9-PIK3CAm CRISPR cell pools compared to PC9 parental cells, indicating activation of downstream PI3K / AKT and MAPK signaling pathways in cells resistant to osimertinib. Treatment with osimertinib downregulated P-EGFR levels and MAPK signaling in both parental and PC9-PIK3CAm cells. However, in PC9-PIK3CAm cells, P-AKT and P-S6 levels were refractory to osimertinib treatment and could be partially reduced in a dose-dependent manner by co-treatment with osimertinib + capivasertib (Figure 6, PC9 and PC9 PIK3CAm cells treated with 160 nM osimertinib alone or in combination with 100 nM-300 nM-1 μM capivasertib for 4 h).

[0176] Example 2: Loss of PTEN promotes resistance to osimertinib in vitro, which can be overcome by combination treatment with capivasertib. To preclinically test the hypothesis that loss of PTEN promotes resistance to osimertinib, we deleted PTEN in two NSCLC cell lines (PC9 and HCC-827) by CRSIPR KO. DNA sequencing and WB analysis confirmed that the loss of PTEN in the generated PC9 cell lines and HCC-827 KO Loss of PTEN in ("PTEN knockout") cell lines was confirmed and resistance to osimertinib and rescue by combination with capivasertib was assessed by:

[0177] a) Cell viability: CTG (osimertinib 3 nM to 10 μM treatment, 6 days) reduced cell viability in HCC-827 PTEN KO cell lines and PC9 PTEN KO The sensitivity of the cell lines to osimertinib was compared with that of the parental cells. KO The cell lines exhibited resistance to osimertinib, as indicated by an increased EC50 of osimertinib, when compared to the parental HCC-827 cells (Figure 7). After 2–3 weeks of osimertinib treatment, PC9 PTEN KO The cells showed similar sensitivity to osimertinib when compared to the PC9 parental cells, and resistance emerged later (Figure 8). In this PC9 model, resistance was observed in PC9 PTEN cells treated with 160 nM osimertinib for 3 weeks compared to PC9 cells that had the same osimertinib exposure (PC9 NTC osimertinib, 3 weeks). KO This is associated with an increased EC50 in cells.

[0178] b) Clonogenic assay: HCC-827 PTEN treated with 160 nM osimertinib KO Cell lines and PC9 PTEN KO The proliferation of the cell lines was compared to the parental cells in a long-term assay. 3Cells were seeded at low density in 6-well plates and treated with 160 nM osimertinib, and cell density (% surface) was calculated at the end of treatment. After 3 weeks, HCC-827 PTEN KO The cells were more dense (20x) than the parental HCC-827, indicating that loss of PTEN resulted in osimertinib resistance. Co-treatment with 500 nM capivasertib resulted in partial rescue of osimertinib resistance (Figure 9). In the PC9 model, PC9 PTEN was downregulated when compared to the parental PC9 cells. KO A milder resistance phenotype was observed with only a 2× higher cell density (FIG. 10).

[0179] c) Intracellular changes by WB analysis. Protein analysis by Western blot showed that PC9 PTEN KO and HCC-827 PTEN KO Both HCC-827 and PTEN showed increased levels of P-AKT and P-S6. KO Unexpectedly, we also observed increased RAS-MAPK signaling in PC9 PTEN treated with osimertinib 160 nM for 3 weeks (Figure 11). KO Stable p-S6 levels were observed in cells (Figure 12). A dose-dependent downregulation of P-S6 levels was observed with capivasertib in combination with osimertinib (Figures 13 and 14).

[0180] d) Additional observations: - In the in vitro model HCC-827, resistance to osimertinib could be rescued by combination with capivasertib (Figure 15, CTG assay), consistent with the hypothesis that loss of PTEN promotes resistance. - In the in vitro model PC9, the combination of osimertinib + capivasertib was able to mildly sensitize cells to osimertinib (Figure 16, clonogenic assay).

[0181] Example 3: In vivo xenograft model Additionally, an in vivo model using patient-derived cell lines was used to investigate the activity of the combination.

[0182] a) PC9 PIKC3A H1047 Cell lines and PC9 PIKC3A E453K The cell lines were cultured in RPMI1640 supplemented with 10% FCS and incubated in a humidified incubator with 5% CO2 at 37°C. PC9 PIKC3A H1047 Xenografts and PC9 PIKC3A E453K Xenografts were implanted into the flanks of female NOD / SCID mice at 5 × 10 cells per animal in 100 μL of cell suspension containing 50% Matrigel. 6 Cells were established by subcutaneous implantation. All mice were over 6 weeks old at the time of cell implantation. Tumor growth was monitored twice weekly by bilateral caliper measurement, and tumor volume was calculated using the formula: TV (mm3) = [length (mm) x width (mm)2] x 0.5 (length and width are the longest and shortest diameters of the tumor).

[0183] PC9 PIKC3A H1047 and PC9 PIKC3A E453 is a CRISPR engineered cell line. Figures 17 and 18 show that the combination of an EGFR TKI with an AKT inhibitor enhances the response to treatment and slows growth even when treatment is stopped.

[0184] b) LC-F-12 tumor fragments from donor mice inoculated with primary human lung cancer tissue were collected and inoculated subcutaneously into the flanks of female athymic nude mice. Tumor growth was monitored twice weekly by bilateral caliper measurements, and tumor volume was calculated using the formula TV (cm3) = [length (cm) x width (cm)2] x 0.5 (length and width are the longest and shortest diameters of the tumor).

[0185] LC-F-12 is a PDX model derived from a patient who had not been treated with TKI. Figure 19 shows that the combination of EGFR TKI and AKT inhibitor enhances the response to treatment and delays growth even after treatment is stopped.

[0186] c) MR131 and CTG-2939 tumor fragments from donor mice inoculated with primary human lung cancer tissue were collected and inoculated subcutaneously into the flanks of female NSG mice. Tumor growth was monitored twice weekly by bilateral caliper measurements, and tumor volumes were measured as TV (cm). 3 ) = [length (cm) × width (cm)2] × 0.5 (length and width are the longest and shortest diameters of the tumor).

[0187] Figure 20 shows that the combination of an EGFR TKI and an AKT inhibitor induces tumor growth stasis in MR131, a model of acquired resistance due to loss of PTEN. Similarly, Figure 21 shows that the combination exhibits superior activity and induces tumor growth stasis compared to EGFR TKI monotherapy in CTG-2939, a model of acquired resistance due to loss of PTEN.

[0188] d) CTG-2180 tumor fragments from donor mice inoculated with primary human lung cancer tissue were collected and inoculated subcutaneously into the flanks of female athymic nude mice. Tumor growth was monitored twice weekly by bilateral caliper measurements, and tumor volumes were expressed as TV (cm). 3 ) = [length (cm) x width (cm) 2 ]×0.5 (where length and width are the longest and shortest diameters of the tumor).

[0189] FIG. 22 shows that the combination of an EGFR TKI with an AKT inhibitor induces superior tumor regression compared to EGFR TKI monotherapy in CTG-2180, a PDX model derived from a TKI-naive patient.

[0190] e) PC9 PTEN-KO and HCC827 PTEN-KO cell lines were cultured in RPMI1640 supplemented with 10% FCS and incubated in a humidified incubator with 5% CO2 at 37°C. PC9 PTEN-KO and HCC827 PTEN-KO xenografts were implanted into the flanks of female NOD / SCID and nude mice, respectively, at 5 × 10 cells per animal in 100 μL of cell suspension containing 50% Matrigel. 6 Cells were established by subcutaneous implantation. All mice were over 6 weeks old at the time of cell implantation. Tumor growth was monitored twice weekly by bilateral caliper measurement, and tumor volumes were calculated as TV (mm 3 ) = [length (mm) × width (mm)2] × 0.5 (where length and width are the longest and shortest diameters of the tumor).

[0191] Figure 23 shows that there is no evidence of benefit of combining osimertinib and capivasertib in the PTEN KO CRISPR engineered model in vivo, and Figure 24 shows that the degree of resistance to osimertinib in the PC9 / HCC827 PTEN KO model in vivo is minimal at best, thus limiting the opportunity to detect combination benefit.

Claims

[Claim 1] The invention described in the present specification and drawings.

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