Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in combination with AKT inhibitors for treatment of cancer

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 EGFR TKI is administered in combination with an AKT inhibitor.

Description

Technical Field

[0001] The present disclosure relates to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for use in treating cancer (eg, non-small cell lung cancer [NSCLC]), wherein the EGFR TKI is administered in combination with an AKT inhibitor. Background Art

[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 were associated with responses to EGFR-TKI therapy in NSCLC (Science [Science]

[2004] , Vol. 304, 1497-1500; New England Journal of Medicine

[2004] , Vol. 350, 2129-2139). It is estimated that these mutations are prevalent in approximately 10%-16% of American and European NSCLC patients and approximately 30%-50% of Asian NSCLC patients. Two of the most significant EGFR activating mutations are exon 19 deletions and missense mutations in exon 21. Exon 19 deletions account for approximately 45% of known EGFR mutations. Eleven different mutations resulting in deletions of three to seven amino acids have been detected in exon 19, all of which are centered on the codon for the consistent deletion of amino acids 747-749. The most significant exon 19 deletion is E746-A750. Missense mutations in exon 21 account for approximately 39%-45% of known EGFR mutations, with the substitution mutation L858R accounting for approximately 39% of the total mutations in exon 21 (J. Thorac. Oncol. [Journal of Thoracic Oncology]

[2010] , 1551-1558).

[0003] There are currently 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) available for the management of EGFR mutation-positive NSCLC. All of these TKIs are effective in NSCLC patients whose tumors carry in-frame deletions in exon 19 and L858R point mutations 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 (regardless of the presence or absence of T790M mutations). However, even patients treated with osimertinib will eventually progress, mainly due to the development of acquired resistance caused by other resistance mechanisms. Therefore, there remains a need to develop new therapies for the treatment of NSCLC, especially for patients whose disease has progressed after treatment with third-generation EGFR TKIs.

[0004] Induction of programmed cell death via apoptosis is a key mechanism of anticancer action of osimertinib and other EGFR TKIs. However, some cancers may be resistant to (or intrinsically possess) such apoptosis, thereby reducing the effectiveness of treatment.

[0005] Laboratory experiments using a population of cancer cells sensitive to osimertinib have shown that the combined use of AKT inhibitors can enhance the effects of EGFR TKIs in some patients. AKT is a serine / threonine-specific protein kinase that plays a key role in a variety of cellular processes, such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. Mammalian cells express three closely related AKT isoforms, which are encoded by different genes: AKT1 (protein kinase Bα), AKT2 (protein kinase Bβ), and AKT3 (protein kinase Bγ). Examples of AKT inhibitors include capasitinib (also known as AZD5363, chemical name (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide) or a pharmaceutically acceptable salt thereof, which is a selective inhibitor of all three AKT isoforms.

[0006] Without being bound by theory, it is proposed that in cancer cells that are dependent on the EGFR pathway, inhibition of this protein may induce a state in which the cells are susceptible to AKT inhibitors. Cells that survive long-term treatment with EGFR TKI monotherapy may have cell death defects and serve as a reservoir for the development of clinical resistance. However, in a subset of these patients, the cellular adaptations required for cancer cells to avoid death in the presence of EGFR inhibition may reveal novel vulnerabilities to AKT inhibitors.

[0007] In preclinical cell line models, a subset of cells that were resistant to osimertinib showed enhanced sensitivity to AKT inhibitors compared to parental cells that were sensitive to osimertinib. This allows the combination of AKT and osimertinib to overcome established resistance, providing a potential avenue for treating patients whose cancer no longer responds to EGFR TKIs alone.

[0008] Therefore, it has been determined that treatment with AKT inhibitors can overcome such resistance, thereby resensitizing the cancer to the apoptotic effects of EGFR TKIs. In addition, the combination of EGFR inhibitors and AKT inhibitors may work together in therapy to prevent resistance or delay its onset. Summary of the invention

[0009] The present disclosure provides a means of utilizing an AKT inhibitor in combination with an EGFR TKI to enhance the anti-proliferative and pro-apoptotic effects of EGFR TKI treatment in cancer (eg, NSCLC).

[0010] Thus, the present specification discloses a combination of an EGFR TKI and an AKT inhibitor as both a first-line treatment for EGFR mutant NSCLC (i.e., in EGFR TKI-naive patients) and as a treatment for its minimal residual disease stage (i.e., in patients previously treated with EGFR TKI, where combination therapy is initiated at the point of maximum drug response, where the number of remaining tumor cells may be so small that they do not cause any signs or symptoms).

[0011] In one aspect, an EGFR TKI for use in treating cancer in a human patient is provided, wherein the EGFR TKI is administered in combination with an AKT inhibitor.

[0012] The terms "treat, treating and treatment" refer to at least partially alleviating, inhibiting, preventing and / or alleviating a condition, disorder or disease (such as lung cancer). The term "treatment of cancer" includes both in vitro and in vivo treatments (including in warm-blooded animals (such as humans)). The effective performance of cancer treatment is evaluated in a variety of ways, including but not limited to: inhibiting cancer cell proliferation (including reversing cancer growth); promoting cancer cell death (for example, by promoting apoptosis or another cell death mechanism); improving symptoms; the duration of response to treatment; delaying the progression of the disease; and prolonging survival. Treatment can also be evaluated with respect to the nature and extent of side effects associated with the treatment. In addition, effectiveness can be evaluated with respect to biomarkers (such as expression levels or phosphorylation levels of proteins known to be associated with specific biological phenomena). Other ways of evaluating effectiveness are known to those skilled in the art.

[0013] The phrase "in combination with" and similar terms (including "concurrently") encompass the administration of two or more active pharmaceutical ingredients to a subject, and includes administration simultaneously in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active pharmaceutical ingredients are present.

[0014] In a further aspect, there is provided use of an EGFR TKI in the preparation of a medicament for treating cancer in a human patient, wherein the EGFR TKI is administered in combination with an AKT inhibitor.

[0015] In additional aspects, methods of treating cancer in a human patient in need of such treatment are provided, the method 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.

[0016] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or combination of compounds as described herein that is sufficient to affect the intended application (including but not limited to disease treatment). The therapeutically effective amount can vary depending on the intended application (in vitro or in vivo) or the subject and disease condition being treated (e.g., the subject's weight, age and gender), the severity of the disease condition, the mode of administration, etc., which can be easily determined by one of ordinary skill in the art. The term also applies to a dose that will induce a specific response in the target cell (e.g., the amount of apoptosis). The specific dose will vary depending on the specific compound selected, the dosage regimen to be followed, whether the compound is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system that carries the compound.

[0017] In additional aspects, methods of treating cancer in a human patient in need of such treatment are provided, the method 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.

[0018] In a further aspect, a pharmaceutical composition comprising an EGFR TKI, an AKT inhibitor and a pharmaceutically acceptable excipient is provided.

[0019] The term "pharmaceutically acceptable" is used to specify that an object (e.g., salt, dosage form, or excipient [such as a diluent or carrier]) is suitable for use in a patient. A list of examples of pharmaceutically acceptable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use", PH Stahl and CG Wermuth, eds., Weinheim / Zurich: Wiley-VCH / VFiCA, 2002 or subsequent editions.

[0020] 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.

[0021] In a further aspect, an AKT inhibitor for use in treating cancer in a human patient is provided, wherein the AKT inhibitor is administered in combination with an EGFR TKI. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 : Compared with parental PC9 cells, PC9PIK3CA H1047R and PC9PIK3CA E453K Cell viability assay (CTG). PC9PIK3CAm cells are more resistant to osimertinib (A).

[0023] Figure 2 : Compared with parental PC9 cells, PC9 PIK3CA H1047R Cell viability assay (CTG). PC9PIK3CAm cells were more resistant to osimertinib and could be partially resensitized using co-treatment with 500 nM AZD5363.

[0024] Figure 3 : Compared with parental PC9 cells, PC9 PIK3CA E453K Cell viability assay (CTG). PC9PIK3CAm cells were more resistant to osimertinib and could be partially resensitized using co-treatment with 500 nM AZD5363.

[0025] Figure 4 : PC9PIK3CA expression was upregulated compared with PC9 parental cells as determined by caspase 3 / 7 activation H1047R Osimertinib-mediated apoptotic response in PC9 cells cannot be restored by co-treatment with AZD5363 H1047R Attenuated apoptotic response in cells.

[0026] Figure 5 Figure : Clonogenicity assay of PC9 PIK3CAm compared with parental PC9 cells. PC9-PIK3CAm cells developed resistance to osimertinib, which could be partially rescued by combination with capasitinib.

[0027] Figure 6 : WB analysis of PC9 PIK3CAm cells treated with 160 nM osimertinib alone or in combination with capasitinib for 4 h.

[0028] Figure 7 : Compared with parental cells, two different HCC-827 PTEN KO Cell viability of cell lines (CTG). Compared with parental cells, HCC-827PTEN KO The cells were more resistant to osimertinib.

[0029] Figure 8 : PC9PTEN expression in naive or osimertinib-exposed PC9PTEN cells was significantly higher than that in parental cells. KO Cell viability of cell lines (CTG). After 3 weeks of drug selection, PC9 PTEN KO Develop resistance.

[0030] Fig. 9 PC9 PTEN cells were treated with osimertinib 160 nM alone or in combination with 500 nM AZD5363 for 3 or 5 weeks. KO Cell clonogenicity assay. PTENK O cells developed resistance, which could be partially resensitized by combination with capasitinib.

[0031] Fig.10 : HCC-827 PTEN treated with osimertinib 160 nM alone or in combination with 500 nM AZD5363 for 3 or 5 weeks KO Cell clonogenicity assay. PTEN KO Cells developed resistance, which could be partially resensitized by combination with capasitinib.

[0032] Fig.11 : Compared with parental cells, HCC-827 PTEN KO Intracellular changes of WB analysis of cell lines.

[0033] Fig.12 : Compared with parental cells, PC9 PTEN KO Intracellular changes by WB analysis of cell lines (naive or exposed to 160 nM osimertinib for 3 weeks).

[0034] Fig.13 : HCC-827 PTEN treated with capasitinib (as monotherapy) KO Intracellular changes of WB analysis of cell lines.

[0035] Fig.14 : HCC-827 PTEN treated with capasitinib (in combination with osimertinib therapy) KO Intracellular changes of WB analysis of cell lines.

[0036] Fig.15 : Cell viability assay (CTG) of HCC-827 cells treated with osimertinib (3 nM-10 mM) alone or in combination with 500 nM capasitinib.

[0037] Fig.16 : 2 different PC9 PTEN treated with osimertinib alone or in combination with capasitinib or PI3K inhibitors compared with parental NTC cells KO The clonogenicity assay of PC9PTEN was performed (upper panel). KO Cells became resistant to osimertinib and were partially resensitized by capasitinib.

[0038] Fig.17 : In PC9 PIKC3A H1047 Combination effect of EGFR TKI and AKT inhibitor in xenograft models.

[0039] Fig.18 : In PC9 PIKC3AE453K Combination effect of EGFR TKI and AKT inhibitor in xenograft models.

[0040] Fig.19 : LC-F-12PIKC3A E545K Combination effect of EGFR TKI and AKT inhibitor in xenograft models.

[0041] Fig. 20 :In MR131 PTEN D326H Combination effect of EGFR TKI and AKT inhibitor in xenograft models.

[0042] Fig.21 :CTG-2939PTEN DeepDel Combination effects of EGFR TKI and AKT inhibitor in xenograft models.

[0043] Fig. 22 :CTG-2180PTEN C304fs Combination effect of EGFR TKI and AKT inhibitor in xenograft models.

[0044] Fig.23 : In PC9PTEN KO Combination effect of EGFR TKI and AKT inhibitor in xenograft models.

[0045] Fig.24 : In HCC-827PTEN KO Combination effect of EGFR TKI and AKT inhibitor in xenograft models. DETAILED DESCRIPTION

[0046] EGFR mutation-positive NSCLC, patient selection, and diagnostic approach

[0047] In embodiments, the cancer comprises a PIK3CA mutation (e.g., a gain-of-function mutation or a deletion, substitution, or insertion mutation, such as PIK3CA H1047R Mutation, PIKC3A E453K Mutation, PI3K E542K Mutation or PIKC3A E545K Mutation). The PI3KCA mutation status can be determined by methods known in the art.

[0048] 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) in which normal amounts of a PTEN tumor suppressor protein [e.g., compared to non-cancerous cells of the same patient] or function are reduced). PTEN status can be determined by methods known in the art.

[0049] In embodiments, the cancer is lung cancer, such as non-small cell lung cancer (NSCLC).

[0050] In embodiments, the NSCLC is EGFR mutation-positive NSCLC.

[0051] In an embodiment, the EGFR mutation-positive NSCLC comprises an activating mutation in EGFR. In another embodiment, the EGFR mutation-positive NSCLC comprises a non-resistant mutation. In another embodiment, the activating mutation in EGFR comprises an activating mutation in exons 18-21. In another embodiment, the activating mutation in EGFR comprises an exon 19 deletion or a missense mutation in exon 21. In another embodiment, the activating mutation in EGFR comprises an exon 19 deletion or an L858R substitution mutation. In another embodiment, the mutation in EGFR comprises a T790M mutation.

[0052] In embodiments, the EGFR mutation-positive NSCLC is locally advanced EGFR mutation-positive NSCLC.

[0053] In embodiments, the EGFR mutation-positive NSCLC is metastatic EGFR mutation-positive NSCLC.

[0054] In embodiments, the EGFR mutation-positive NSCLC is not amenable to curative surgery or radiation therapy.

[0055] Technicians will recognize that there are many methods for detecting EGFR activating mutations. A plurality of tests suitable for use in these methods have been approved by the U.S. Food and Drug Administration (FDA). These include diagnostic methods based on tumor tissue and plasma-based diagnostic methods. Typically, a tumor tissue biopsy sample derived from a human patient is first used to assess EGFR mutation status. If a tumor sample is unavailable, or if the tumor sample is negative, a plasma sample can be used to assess EGFR mutation status. A specific example of a suitable diagnostic test for detecting EGFR mutations, particularly for detecting exon 19 deletions, L858R substitution mutations and T790M mutations is Cobas TM EGFR Mutation Test v2 (Roche Molecular Diagnostics).

[0056] Thus, in embodiments, EGFR mutation-positive NSCLC comprises an activating mutation in EGFR (e.g., an activating mutation in exon 18-21, e.g., exon 19 deletion, missense mutation in exon 21, and L858R substitution mutation; and resistance mutations such as T790M mutation), wherein an appropriate diagnostic test has been used to determine the EGFR mutation status of the human patient. In further embodiments, a tumor tissue sample has been used to determine the EGFR mutation status. In further embodiments, a plasma sample has been used to determine the EGFR mutation status. In further embodiments, the diagnostic method uses an FDA-approved test. In further embodiments, the diagnostic method uses a Cobas TM EGFR mutation testing (v1 or v2).

[0057] In embodiments, the human patient is an EGFR TKI naive human patient.

[0058] In an embodiment, the human patient has previously received EGFR TKI treatment. In an embodiment, the human patient has previously been treated with osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient's disease has reached the maximum response (micro-residual disease) stage during or after the previous EGFR TKI treatment. In a further embodiment, the human patient's disease has reached the maximum response during or after the previous treatment with osimertinib or a pharmaceutically acceptable salt thereof. EGFR TKI treatment includes treatment with first-generation, second-generation, or third-generation EGFR TKI or a combination thereof. In an embodiment, EGFR T790M mutation-positive NSCLC has occurred in the human patient.

[0059] EGFR TKI

[0060] EGFR TKIs can be characterized as first-generation, second-generation, or third-generation EGFR TKIs, as described below.

[0061] First generation EGFR TKIs are reversible inhibitors of EGFR with activating mutations that do not significantly inhibit EGFR with the T790M mutation. Examples of first generation TKIs include gefitinib and erlotinib.

[0062] Second-generation EGFR TKIs are irreversible inhibitors of EGFR with activating mutations, which do not significantly inhibit EGFR with the T790M mutation. Examples of second-generation TKIs include afatinib and dacomitinib.

[0063] The third generation of EGFR TKI is an inhibitor of EGFR with activating mutations, which also significantly inhibits EGFR with T790M mutation, but does not significantly inhibit wild-type EGFR. Examples of third generation TKIs include compounds with formula (I), osimertinib, AZD3759 (zorifertinib), lazertinib, nazartinib (EGF816), CO1686 (rociletinib), HM61713 (olmutinib), ASP8273 (naquotinib), PF-06747775 (Marwell), The drugs include mavelertinib (mavelertinib), avitinib (abivertinib), alflutinib (AST2818), CX-101 (olafertinib; RX-518), aumelinib (HS-10296; almonertinib), and BPI-7711 (rezivertinib).

[0064] In one aspect, the EGFR TKI is a first generation EGFR TKI. In further embodiments, the first generation EGFR TKI is selected from the group consisting of gefitinib or a pharmaceutically acceptable salt thereof, icotinib or a pharmaceutically acceptable salt thereof, and erlotinib or a pharmaceutically acceptable salt thereof.

[0065] In one aspect, the EGFR TKI is a second generation EGFR TKI. In a further aspect, the second generation EGFR TKI is selected from dacomitinib or a pharmaceutically acceptable salt thereof and afatinib or a pharmaceutically acceptable salt thereof.

[0066] In one aspect, the EGFR TKI is a third generation EGFR TKI. In another aspect, the third generation EGFR TKI is a compound having formula (I) as defined below. In another aspect, 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, avitinib or a pharmaceutically acceptable salt thereof, afatinib 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 another aspect, the third generation EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof.

[0067] Compounds having formula (I)

[0068] In one aspect, EGFRTKI is a compound having formula (I):

[0069]

[0070] in:

[0071] 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;

[0072] R 1 is selected from hydrogen, fluorine, chlorine, methyl and cyano;

[0073] R 2 is selected from the group consisting of methoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy and methyl;

[0074] R 3 selected from (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]octan-2-yl, (3aR,6aR)-5-methylhexa Hydrogen-pyrrolo[3,4-b]pyrrol-1(2H)-yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperazin-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-aminopropionyl]piperazin-1-yl;

[0075] R 4 is selected from hydrogen, 1-piperidinylmethyl and N,N-dimethylaminomethyl;

[0076] R 5 independently selected from methyl, ethyl, propyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro and cyclopropyl;

[0077] X is CH or N; and

[0078] n is 0, 1, or 2;

[0079] or a pharmaceutically acceptable salt thereof.

[0080] In a further aspect, there is provided a 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, fluorine, chlorine, 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 4 is hydrogen; 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 pharmaceutically acceptable salt thereof.

[0081] Examples of compounds having 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.

[0082] Osimertinib and its pharmaceutical composition

[0083] Osimertinib has the following chemical structure:

[0084]

[0085] The chemical name of the free base of osimertinib is known: 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 WO2013 / 014448. Osimertinib is also known as AZD9291.

[0086] Osimertinib is available in the form of a mesylate salt as follows: 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 TM .

[0087] Osimertinib mesylate is currently approved as a once-daily oral tablet formulation at a dose of 80 mg (expressed as free base, equivalent to 95.4 mg osimertinib mesylate) for the treatment of metastatic EGFR T790M mutation-positive NSCLC patients. If the dose needs to be modified, a 40 mg once-daily oral tablet formulation (expressed as free base, equivalent to 47.7 mg osimertinib mesylate) can be used. The core contains a drug diluent (such as mannitol and microcrystalline cellulose), a disintegrant (such as low-substituted hydroxypropyl cellulose) and a lubricant (such as sodium stearyl fumarate). The tablet formulation is described in WO2015 / 101791.

[0088] Thus, in one aspect, osimertinib or a pharmaceutically acceptable salt thereof is in the form of a methanesulfonate salt, i.e., N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide methanesulfonate.

[0089] In one aspect, osimertinib or a pharmaceutically acceptable salt thereof is administered once daily. In another aspect, osimertinib mesylate is administered once daily.

[0090] In one aspect, the total daily dose of osimertinib is about 80 mg. In another aspect, the total daily dose of osimertinib mesylate is about 95.4 mg.

[0091] In one aspect, the total daily dose of osimertinib is about 40 mg. In another aspect, the total daily dose of osimertinib mesylate is about 47.7 mg.

[0092] In one aspect, osimertinib or a pharmaceutically acceptable salt thereof is in the form of a tablet.

[0093] In one aspect, osimertinib or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients (e.g., diluents or carriers). In another aspect, the composition comprises one or more pharmaceutical diluents (e.g., mannitol and microcrystalline cellulose), one or more pharmaceutical disintegrants (e.g., low-substituted hydroxypropyl cellulose), or one or more pharmaceutical lubricants (e.g., sodium stearyl fumarate).

[0094] In one aspect, the composition is in the form of a tablet, wherein the core comprises: (a) from 2 to 70 parts of osimertinib or a pharmaceutically acceptable salt thereof; (b) from 5 to 96 parts of two or more drug diluents; (c) from 2 to 15 parts of one or more drug disintegrants; and (d) from 0.5 to 3 parts of one or more drug lubricants; and wherein all parts are by weight, and the sum of the parts (a) + (b) + (c) + (d) = 100.

[0095] In one aspect, the composition is in the form of a tablet, wherein the core comprises: (a) from 7 to 25 parts of osimertinib or a pharmaceutically acceptable salt thereof; (b) from 55 to 85 parts of two or more drug diluents, wherein the drug diluents comprise microcrystalline cellulose and mannitol; (c) from 2 to 8 parts of a drug disintegrant, wherein the drug disintegrant comprises low-substituted hydroxypropyl cellulose; (d) from 1.5 to 2.5 parts of a drug lubricant, wherein the drug lubricant comprises sodium stearyl fumarate; and wherein all parts are by weight, and the sum of the parts (a) + (b) + (c) + (d) = 100.

[0096] In one aspect, the composition is in the form of a tablet, wherein the core comprises: (a) about 19 parts of osimertinib mesylate; (b) about 59 parts of mannitol; (c) about 15 parts of microcrystalline cellulose; (d) about 5 parts of low-substituted hydroxypropyl cellulose; and (e) about 2 parts of sodium stearyl fumarate; and wherein all parts are by weight, and the sum of the parts (a) + (b) + (c) + (d) + (e) = 100.

[0097] AZD3759 (Zolitinib)

[0098] AZD3759 has the following chemical structure:

[0099]

[0100] 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 WO2014 / 135876.

[0101] In one aspect, AZD3759 or a pharmaceutically acceptable salt thereof is administered twice daily.In a further aspect, AZD3759 is administered twice daily.

[0102] In one aspect, the total daily dose of AZD3759 is about 400 mg. In a further aspect, about 200 mg of AZD3759 is administered twice daily.

[0103] Lazertinib

[0104] Lazertinib has the following chemical structure:

[0105]

[0106] The chemical name of the free base of lazertinib is known as 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 WO2016 / 060443. Lazertinib is also known as YH25448 and GNS-1480.

[0107] In one aspect, lazertinib or a pharmaceutically acceptable salt thereof is administered once daily. In another aspect, lazertinib is administered once daily.

[0108] In one aspect, the total daily dose of lazertinib is about 20 to 320 mg.

[0109] In one aspect, the total daily dose of lazertinib is about 240 mg.

[0110] Avitinib

[0111] Avitinib has the following chemical structure:

[0112]

[0113] The chemical name of the free base of Avitinib is known as: 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 US2014038940. Avitinib is also known as Avitinib.

[0114] In one aspect, avitinib or a pharmaceutically acceptable salt thereof is administered twice daily. In another aspect, avitinib maleate is administered twice daily.

[0115] In one aspect, the total daily dose of avitinib maleate is about 600 mg.

[0116] Afatinib

[0117] Afatinib has the following chemical structure:

[0118]

[0119] The chemical name of the free base of Afatinib is known as: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxy)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide. Afatinib is disclosed in WO2016 / 15453. Afatinib is also known as AST2818.

[0120] In one aspect, afatinib or a pharmaceutically acceptable salt thereof is administered once daily. In another aspect, afatinib mesylate is administered once daily.

[0121] In one aspect, the total daily dose of afatinib mesylate is about 80 mg.

[0122] In one aspect, the total daily dose of afatinib mesylate is about 40 mg.

[0123] Afatinib

[0124] Afatinib has the following chemical structure:

[0125]

[0126] The chemical name of the free base of afatinib is known as: N-[4-(3-chloro-4-fluoroanilino)-7-[(3S)-oxolan-3-yl]oxyquinazolin-6-yl]-4-(dimethylamino)but-2-enamide. Afatinib is disclosed in WO02 / 50043. Afatinib is also known as Gilotrif.

[0127] In one aspect, afatinib or a pharmaceutically acceptable salt thereof is administered once daily. In another aspect, afatinib dimaleate is administered once daily.

[0128] In one aspect, the total daily dose of afatinib dimaleate is about 40 mg.

[0129] In one aspect, the total daily dose of afatinib dimaleate is about 30 mg.

[0130] CX-101

[0131] CX-101 has the following chemical structure:

[0132]

[0133] The chemical name of the free base of CX-101 is known as: 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 WO2015 / 027222. CX-101 is also known as RX-518 and Olavinib. HS-10296 (almonertinib, aumolertinib)

[0134] HS-10296 (almonertinib, aumolertinib) has the following chemical structure:

[0135]

[0136] The chemical name of the free base of HS-10296 is known as: 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 WO2016 / 054987.

[0137] In one aspect, the total daily dose of HS-10296 is about 110 mg.

[0138] BPI-7711 (rivulitinib)

[0139] BPI-7711 has the following chemical structure:

[0140]

[0141] The chemical name of the free base of BPI-7711 is known as: 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 WO2016 / 94821.

[0142] In one aspect, the total daily dose of BPI-7711 is about 180 mg.

[0143] Dacomitinib

[0144] Dacomitinib has the following chemical structure:

[0145]

[0146] The chemical name of the free form of dacomitinib is known: (2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-4-(piperidin-1-yl)but-2-enamide. Dacomitinib is described in WO2005 / 107758. Dacomitinib is also known as PF-00299804.

[0147] Dacomitinib can exist in the form of a dacomitinib monohydrate, namely (2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-4-(piperidin-1-yl)but-2-enamide monohydrate.

[0148] In one aspect, dacomitinib or a pharmaceutically acceptable salt thereof is administered once daily. In another aspect, dacomitinib monohydrate is administered once daily.

[0149] In one aspect, the total daily dose of dacomitinib monohydrate is about 45 mg.

[0150] In one aspect, dacomitinib or a pharmaceutically acceptable salt thereof is in the form of a tablet.

[0151] In one aspect, dacomitinib or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. In another aspect, the one or more pharmaceutically acceptable excipients comprise lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.

[0152] Icotinib

[0153] Icotinib has the following chemical structure:

[0154]

[0155] The chemical name of the free base of icotinib is known to be: N-(3-ethynylphenyl)-2,5,8,11-tetraoxa-15,17-diazatricyclo[10.8.0.0 14,19 ] Eicosapenta-1(12),13,15,17,19-pentaen-18-amine. Icotinib is disclosed in WO2013064128. Icotinib is also known as Conmana.

[0156] In embodiments, icotinib or a pharmaceutically acceptable salt thereof is administered three times daily. In further embodiments, icotinib hydrochloride is administered three times daily.

[0157] In an embodiment, the total daily dose of icotinib hydrochloride is about 375 mg.

[0158] Gefitinib

[0159] Gefitinib has the following chemical structure:

[0160]

[0161] The chemical name of the free base of gefitinib is known as: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine. Gefitinib is disclosed in WO1996 / 033980. Gefitinib is also known as IRESSA TM .

[0162] In embodiments, gefitinib or a pharmaceutically acceptable salt thereof is administered once daily. In further embodiments, gefitinib is administered once daily.

[0163] In an embodiment, the total daily dose of gefitinib is about 250 mg.

[0164] Erlotinib

[0165] Erlotinib has the following chemical structure:

[0166]

[0167] The chemical name of the free base of erlotinib is known as: N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine. Erlotinib is disclosed in WO1996 / 030347. Erlotinib is also known as TARCEVA TM .

[0168] In embodiments, erlotinib or a pharmaceutically acceptable salt thereof is administered once daily. In further embodiments, erlotinib is administered once daily.

[0169] In an embodiment, the total daily dose of erlotinib is about 150 mg.

[0170] In an embodiment, the total daily dose of erlotinib is about 100 mg.

[0171] AKT inhibitors

[0172] In embodiments, an AKT inhibitor is any molecule that binds to and inhibits the activity of one or more AKT isoforms.

[0173] In an embodiment, the AKT inhibitor is selected from the group consisting of miransertib (ARQ-092) or a pharmaceutically acceptable salt thereof, BAY1125976 or a pharmaceutically acceptable salt thereof, borussertib or a pharmaceutically acceptable salt thereof, AT7867 or a pharmaceutically acceptable salt thereof, CCT128930 or a pharmaceutically acceptable salt thereof, A-674563 or a pharmaceutically acceptable salt thereof, PHT-427 or a pharmaceutically acceptable salt thereof, Akti-1 / 2 or a pharmaceutically acceptable salt thereof, AT13148 or a pharmaceutically acceptable salt thereof, SC79 or a pharmaceutically acceptable salt thereof, capasertib or a pharmaceutically acceptable salt thereof, miltefosine or a pharmaceutically acceptable salt thereof. , perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or a pharmaceutically acceptable salt thereof, erucylphosphocholine or a pharmaceutically acceptable salt thereof, PBI-05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, afuresertib (GSK2110183) or a pharmaceutically acceptable salt thereof, uprosertib (GSK2141795) or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof, and ipatasertib (GDC-0068) or a pharmaceutically acceptable salt thereof.

[0174] In an embodiment, the AKT inhibitor is selected from the group consisting of capasitinib or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or a pharmaceutically acceptable salt thereof, sinaphocholine or a pharmaceutically acceptable salt thereof, PBI-05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, eupressant (GSK2141795) or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof, and patasertib or a pharmaceutically acceptable salt thereof.

[0175] In an embodiment, the AKT inhibitor is selected from the group consisting of capasitinib 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, aflotoxin (GSK2110183) or a pharmaceutically acceptable salt thereof, eupressant (GSK2141795) or a pharmaceutically acceptable salt thereof, and patasertib (GDC-0068) or a pharmaceutically acceptable salt thereof.

[0176] Capasitinib

[0177] Capasitinib has the following chemical structure:

[0178]

[0179] The free base of capasitinib 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). Capasitinib is disclosed in WO2009 / 047563, which discloses capasitinib (in Example 9) and describes its synthesis.

[0180] In one aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. In another aspect, the composition comprises one or more pharmaceutical diluents (such as mannitol and microcrystalline cellulose), one or more pharmaceutical disintegrants (such as low-substituted hydroxypropyl cellulose) or one or more pharmaceutical lubricants (such as sodium stearyl fumarate).

[0181] In one aspect, the composition is in the form of a tablet.

[0182] In combination with osimertinib, capasitinib or a pharmaceutically acceptable salt thereof is generally administered to a subject at a daily dose of about 100 mg to about 1600 mg.

[0183] In some embodiments, capasitinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 150 mg to about 1500 mg. In one aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 200 mg to about 1400 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 300 mg to about 1300 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 400 mg to about 1200 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 500 mg to about 1100 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 600 mg to about 1000 mg. In some embodiments, capasitinib or a pharmaceutically acceptable salt thereof is administered to a subject once a day (QD).

[0184] In one aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 100 mg to about 1000 mg.

[0185] In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 150 mg to about 900 mg. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 200 mg to about 850 mg. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 250 mg to about 800 mg. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 300 mg to about 750 mg.

[0186] In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 350 mg to about 700 mg. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 400 mg to about 650 mg.

[0187] In some embodiments, capasitinib or a pharmaceutically acceptable salt thereof is administered to a subject twice daily (BID). In one aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dosage of about 50 mg to about 900 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dosage of about 100 mg to about 875 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dosage of about 200 mg to about 850 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dosage of about 250 mg to about 825 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dosage of about 150 mg to about 250 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dosage of about 250 mg to about 350 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dosage of about 350 mg to about 450 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 450 mg to about 550 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 550 mg to about 650 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 650 mg to about 750 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 750 mg to about 850 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 160 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 240 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 280 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 320 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 360 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 400 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 440 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 480 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 520 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 560 mg. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 600 mg.In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 640 mg. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 680 mg. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 720 mg. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 760 mg. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 800 mg.

[0188] In some embodiments, capasitinib or a pharmaceutically acceptable salt thereof is administered according to a continuous dosing schedule. In one aspect, for example, capasitinib or a pharmaceutically acceptable salt thereof is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, 21, 28, 35, 42, 49 or 56 days. In another aspect, the dosing cycle is 28 days. As long as the subject tolerates and benefits, the administration of capasitinib or a pharmaceutically acceptable salt thereof and the repetition of the dosing cycle can continue.

[0189] In some embodiments, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily (QD) according to a continuous dosing schedule. In one aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 100 mg to about 900 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 150 mg to about 875 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 175 mg to about 850 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 200 mg to about 825 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 225 mg to about 800 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 250 mg to about 750 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 275 mg to about 700 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 300 mg to about 650 mg according to a continuous dosing schedule. In some embodiments, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily (BID) according to a continuous dosing schedule. In one aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 100 mg to about 800 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 150 mg to about 750 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg to about 700 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 225 mg to about 650 mg according to a continuous dosing schedule. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 250 mg to about 650 mg according to a continuous dosing schedule. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 300 mg to about 600 mg according to a continuous dosing schedule. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg to about 300 mg according to a continuous dosing schedule. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 300 mg to about 400 mg according to a continuous dosing schedule.On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 400 mg to about 500 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 500 mg to about 600 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 600 mg to about 700 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 700 mg to about 800 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 160 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 240 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 280 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 320 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 360 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 400 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 440 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 480 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 520 mg according to a continuous dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 580 mg according to a continuous dosing schedule. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 600 mg according to a continuous dosing schedule. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 640 mg according to a continuous dosing schedule. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 680 mg according to a continuous dosing schedule. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 720 mg according to a continuous dosing schedule. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 760 mg according to a continuous dosing schedule.On the other hand, capasitinib or its pharmaceutically acceptable salt is administered twice daily at a dose of about 800 mg according to a continuous dosing schedule. In some embodiments, capasitinib or its pharmaceutically acceptable salt is administered to a subject according to an intermittent dose schedule. For example, the administration of capasitinib or its pharmaceutically acceptable salt according to an intermittent dose schedule may have greater effectiveness and / or tolerability than according to a continuous dosing schedule. In one aspect, capasitinib or its pharmaceutically acceptable salt is administered intermittently with a schedule of giving 1 day / stopping 6 days (i.e., capasitinib or its pharmaceutically acceptable salt is administered for one day, followed by a six-day vacation). On the other hand, capasitinib or its pharmaceutically acceptable salt is administered intermittently with a schedule of giving 2 days / stopping 5 days (i.e., capasitinib or its pharmaceutically acceptable salt is administered for two days, followed by a five-day vacation). On the other hand, capasitinib or its pharmaceutically acceptable salt is administered intermittently with a schedule of giving 3 days / stopping 4 days (i.e., capasitinib or its pharmaceutically acceptable salt is administered for three days, followed by a four-day vacation). On the other hand, capasitinib or its pharmaceutically acceptable salt is intermittently administered with a schedule of giving 4 days / stopping 3 days (i.e., capasitinib or its pharmaceutically acceptable salt is administered for four days, followed by a three-day vacation). On the other hand, capasitinib or its pharmaceutically acceptable salt is intermittently administered with a schedule of giving 5 days / stopping 2 days (i.e., capasitinib or its pharmaceutically acceptable salt is administered for five days, followed by a two-day vacation). On the other hand, capasitinib or its pharmaceutically acceptable salt is intermittently administered with a schedule of giving 6 days / stopping 1 day (i.e., capasitinib or its pharmaceutically acceptable salt is administered for six days, followed by a one-day vacation). Then, as long as the subject tolerates and is beneficial, the dosing cycle of such an embodiment can be repeated. In some embodiments, the dosing cycle is 7 days. In one aspect, the dosing cycle is 14 days. On the other hand, the dosing cycle is 21 days. On the other hand, the dosing cycle is 28 days. On the other hand, the dosing cycle is two months. On the other hand, the dosing cycle is six months. On the other hand, the dosing cycle is one year.

[0190] In some embodiments, the dosing cycle is 28 days, but during the fourth week of the dosing cycle, capasitinib or a pharmaceutically acceptable salt thereof is not co-administered to the subject (i.e., there is a drug holiday for capasitinib or a pharmaceutically acceptable salt thereof during the last week of the dosing cycle).

[0191] In some embodiments, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily (QD) according to an intermittent dosing schedule. In one aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 100 mg to about 900 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 150 mg to about 850 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 175 mg to about 800 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 200 mg to about 750 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 225 mg to about 725 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 250 mg to about 700 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 275 mg to about 675 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 300 mg to about 650 mg according to an intermittent dosing schedule. In some embodiments, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily (BID) according to an intermittent dosing schedule. In one aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 100 mg to about 800 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 150 mg to about 750 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg to about 700 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 225 mg to about 675 mg according to an intermittent dosing schedule. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 250 mg to about 650 mg according to an intermittent dosing schedule. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 300 mg to about 625 mg according to an intermittent dosing schedule. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg to about 300 mg according to an intermittent dosing schedule. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 300 mg to about 400 mg according to an intermittent dosing schedule.On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 400 mg to about 500 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 500 mg to about 600 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 600 mg to about 700 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 700 mg to about 800 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 160 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 200 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 240 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 280 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 320 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 360 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 400 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 440 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 480 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 520 mg according to an intermittent dosing schedule. On the other hand, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 580 mg according to an intermittent dosing schedule. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 600 mg according to an intermittent dosing schedule. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 640 mg according to an intermittent dosing schedule. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 680 mg according to an intermittent dosing schedule. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 720 mg according to an intermittent dosing schedule. In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 760 mg according to an intermittent dosing schedule.In another aspect, capasitinib or a pharmaceutically acceptable salt thereof is administered at a dose of about 800 mg twice daily according to an intermittent dosing schedule.

[0192] Perifosine

[0193] Perifosine has the following chemical structure:

[0194]

[0195] Perifosine is known by the chemical name 1,1-dimethylpiperidinium-4-yloctadecyl phosphate. Perifosine is disclosed in US Pat. No. 8,383,607.

[0196] MK-2206

[0197] MK-2206 has the following chemical structure:

[0198]

[0199] 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 WO 2008070016.

[0200] GSK690693

[0201] GSK690693 has the following chemical structure:

[0202]

[0203] The chemical name of the free base of GSK690693 is known as 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.

[0204] Afosetyl

[0205] Afloxacin (GSK2110183) has the following chemical structure:

[0206]

[0207] The chemical name of the free base of aflotoxin is known as N-[(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide. Aflotoxin is disclosed in WO2008098104.

[0208] Eupressant

[0209] Eupressant (GSK2141795) has the following chemical structure:

[0210]

[0211] The chemical name of the free base of euprosanthi is known as N-[(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide. Euprosanthi is disclosed in WO2008098104.

[0212] Patasetti

[0213] Patasertib has the following chemical structure:

[0214]

[0215] The chemical name of the free base of patasertib is known as 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. Patasertib is disclosed in WO2008006040.

[0216] Other embodiments

[0217] In one aspect, an EGFR TKI for use in treating cancer in a human patient is provided, wherein the EGFR TKI is administered in combination with an AKT inhibitor. In an embodiment, the cancer is lung cancer, such as NSCLC. In yet further embodiments, the NSCLC is EGFR mutation-positive NSCLC.

[0218] In one aspect, a method of treating cancer in a human patient in need of such treatment is provided, the method 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. In an embodiment, the cancer is lung cancer, such as NSCLC. In yet another embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0219] In one aspect, a method of treating cancer in a human patient in need of such treatment is provided, the method 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. In an embodiment, the cancer is lung cancer, such as NSCLC. In yet another embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0220] In one aspect, there is provided the use of an EGFR TKI in the preparation 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 yet another embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0221] In one aspect, a combination of EGFR TKI and AKT inhibitor for use in treating cancer in human patients is provided. In an embodiment, EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In another embodiment, the human patient is an EGFR TKI-naive human patient. In another embodiment, the human patient has previously received EGFR TKI treatment. In another embodiment, the human patient has previously received osimertinib or a pharmaceutically acceptable salt thereof. In still another embodiment, the cancer is lung cancer, such as NSCLC. In yet another embodiment, NSCLC is EGFR mutation-positive NSCLC.

[0222] On the one hand, a method for treating cancer in a human patient in need of such treatment is provided, the method comprising administering to the human patient 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 pharmaceutically acceptable salt thereof. In another embodiment, the human patient is an EGFR TKI-naive human patient. In another embodiment, the human patient has previously received EGFR TKI treatment. In another embodiment, the human patient has previously received osimertinib or a pharmaceutically acceptable salt thereof. In still another embodiment, the cancer is lung cancer, such as NSCLC. In yet another embodiment, NSCLC is EGFR mutation-positive NSCLC.

[0223] In one aspect, a method for treating cancer in a human patient in need of such treatment is provided, the method 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. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In another embodiment, the human patient is an EGFR TKI-naive human patient. In another embodiment, the human patient has previously received EGFR TKI treatment. In another embodiment, the human patient has previously received osimertinib or a pharmaceutically acceptable salt thereof. In still another embodiment, the cancer is lung cancer, such as NSCLC. In yet another embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0224] In one aspect, a combination of EGFR TKI and AKT inhibitor is provided for the preparation 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 another embodiment, the human patient is an EGFR TKI-naive human patient. In another embodiment, the human patient has previously received EGFR TKI treatment. In another embodiment, the human patient has previously received osimertinib or a pharmaceutically acceptable salt thereof. In still another embodiment, the cancer is lung cancer, such as NSCLC. In yet another embodiment, NSCLC is EGFR mutation-positive NSCLC.

[0225] In one aspect, a combination of osimertinib or a pharmaceutically acceptable salt thereof and an AKT inhibitor for use in treating cancer in a human patient is provided, wherein osimertinib or a pharmaceutically acceptable salt thereof is administered to the human patient prior to administering the AKT inhibitor to the human patient. In an embodiment, the cancer is lung cancer, such as NSCLC. In yet another embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0226] In one aspect, a method of treating cancer in a human patient in need of such treatment is provided, the method comprising administering to the human patient a therapeutically effective amount of osimertinib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an AKT inhibitor in combination, wherein osimertinib or a pharmaceutically acceptable salt thereof is administered to the human patient prior to administering the AKT inhibitor to the human patient. In embodiments, the cancer is lung cancer, such as NSCLC. In yet further embodiments, the NSCLC is EGFR mutation-positive NSCLC.

[0227] In one aspect, a method of treating cancer in a human patient in need of such treatment is provided, the method 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, wherein prior to administering the AKT inhibitor to the human patient, osimertinib or a pharmaceutically acceptable salt thereof is administered to the human patient. In embodiments, the cancer is lung cancer, such as NSCLC. In yet further embodiments, the NSCLC is an EGFR mutation-positive NSCLC.

[0228] In one aspect, a combination of osimertinib or a pharmaceutically acceptable salt thereof and an AKT inhibitor is provided for use in the preparation of a medicament for treating cancer in a human patient, wherein osimertinib or a pharmaceutically acceptable salt thereof is administered to the human patient prior to administering the AKT inhibitor to the human patient. In an embodiment, the cancer is lung cancer, such as NSCLC. In yet another embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0229] In one aspect, an EGFR TKI for use in treating cancer in a human patient is provided, wherein the treatment comprises administering to the human patient i) an EGFR TKI and ii) an AKT inhibitor separately, sequentially or simultaneously. If the treatment is separate or sequential, the time interval between the EGFR TKI dose and the AKT inhibitor dose can be selected to ensure a combined therapeutic effect.

[0230] A "therapeutic effect" encompasses a therapeutic benefit and / or a prophylactic benefit. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof.

[0231] In embodiments, the EGFR TKI and the AKT inhibitor are administered sequentially, and the EGFR TKI is administered prior to administration of the AKT inhibitor.

[0232] In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the human patient is an EGFR TKI-naive human patient. In a further embodiment, the human patient has previously been treated with EGFR TKI. In a further embodiment, the human patient has previously been treated with osimertinib or a pharmaceutically acceptable salt thereof. In a further embodiment, the cancer is lung cancer, such as NSCLC. In yet another embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0233] In one aspect, a method for treating cancer in a human patient in need of such treatment is provided, the method comprising administering to the human patient, separately, sequentially or simultaneously, i) a therapeutically effective amount of an EGFR TKI and ii) a therapeutically effective amount of an AKT inhibitor. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In another embodiment, the human patient is an EGFR TKI-naive human patient. In another embodiment, the human patient has previously received EGFR TKI treatment. In another embodiment, the human patient has previously received osimertinib or a pharmaceutically acceptable salt thereof. In still another embodiment, the cancer is lung cancer, such as NSCLC. In yet another embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0234] On the one hand, a method for treating cancer in a human patient in need of such treatment is provided, the method comprising administering to the human patient separately, sequentially or simultaneously i) a first amount of EGFR TKI and ii) a second amount of an AKT inhibitor, wherein the first amount and the second amount together constitute a therapeutically effective amount. In an embodiment, EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In another embodiment, the human patient is an EGFR TKI-naive human patient. In another embodiment, the human patient has previously received EGFR TKI treatment. In another embodiment, the human patient has previously received osimertinib or a pharmaceutically acceptable salt thereof. In still another embodiment, the cancer is lung cancer, such as NSCLC. In yet another embodiment, NSCLC is EGFR mutation-positive NSCLC.

[0235] In one aspect, there is provided the use of EGFR TKI in the preparation of a medicament for treating cancer in a human patient, wherein the treatment comprises administering i) EGFR TKI and ii) an AKT inhibitor to the human patient separately, sequentially or simultaneously. In an embodiment, EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In another embodiment, the human patient is an EGFR TKI-naive human patient. In another embodiment, the human patient has previously received EGFR TKI treatment. In another embodiment, the human patient has previously received osimertinib or a pharmaceutically acceptable salt thereof. In still another embodiment, the cancer is lung cancer, such as NSCLC. In yet another embodiment, NSCLC is EGFR mutation-positive NSCLC.

[0236] In one aspect, an AKT inhibitor for use in treating cancer in a human patient is provided, wherein the AKT inhibitor is administered in combination with an EGFR TKI.

[0237] In one aspect, an AKT inhibitor for use in treating cancer in a human patient is provided, wherein the treatment comprises administering to the human patient, separately, sequentially or simultaneously, i) an AKT inhibitor and ii) an EGFR TKI. In an embodiment, the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In another embodiment, the human patient is an EGFR TKI-naive human patient. In another embodiment, the human patient has previously received EGFR TKI treatment. In another embodiment, the human patient has previously received osimertinib or a pharmaceutically acceptable salt thereof. In still another embodiment, the cancer is lung cancer, such as NSCLC. In yet another embodiment, the NSCLC is an EGFR mutation-positive NSCLC.

[0238] In one aspect, there is provided the use of an AKT inhibitor in the preparation of a medicament for treating cancer in a human patient, wherein the treatment comprises administering i) EGFR TKI and ii) AKT inhibitor to the human patient separately, sequentially or simultaneously. In an embodiment, EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof. In another embodiment, the human patient is an EGFR TKI-naive human patient. In another embodiment, the human patient has previously received EGFR TKI treatment. In another embodiment, the human patient has previously received osimertinib or a pharmaceutically acceptable salt thereof. In still another embodiment, the cancer is lung cancer, such as NSCLC. In yet another embodiment, NSCLC is EGFR mutation-positive NSCLC.

[0239] In one aspect, a kit is provided, the kit comprising:

[0240] - a first pharmaceutical composition comprising EGFR TKI and a pharmaceutically acceptable excipient; and

[0241] - A second pharmaceutical composition comprising an AKT inhibitor and a pharmaceutically acceptable excipient.

[0242] In one aspect, an AKT inhibitor for use in treating non-small cell lung cancer in a human patient is provided, wherein the patient's disease has reached a maximum response during or after a previous EGFR TKI treatment. In an embodiment, the human patient has experienced disease progression during or after a previous treatment with osimertinib or a pharmaceutically acceptable salt thereof.

[0243] In one aspect, osimertinib or a pharmaceutically acceptable salt thereof is provided for use in treating non-small cell lung cancer in a human patient, wherein the human patient has experienced disease progression during or after prior treatment with a different EGFR TKI.

[0244] In one aspect, a method for treating non-small cell lung cancer in a human patient in need of such treatment is provided, the method comprising administering a therapeutically effective amount of an AKT inhibitor to the human patient, wherein the patient has experienced disease progression during or after prior EGFR TKI treatment. In an embodiment, the human patient has experienced disease progression during or after prior treatment with osimertinib or a pharmaceutically acceptable salt thereof.

[0245] In one aspect, there is provided a use of an AKT inhibitor in the preparation of a medicament for treating non-small cell lung cancer in a human patient, wherein the patient has experienced disease progression during or after a previous EGFR TKI treatment. In an embodiment, the human patient has experienced disease progression during or after a previous treatment with osimertinib or a pharmaceutically acceptable salt thereof.

[0246] Examples

[0247] The following specific examples are provided, with reference to the accompanying drawings, for illustrative purposes only and should not be construed as limiting the teachings herein.

[0248] PC9 is a cell line derived from a human lung adenocarcinoma carrying an activating mutation (Ex19-del) in EGFRdelE746_A750. HCC-827 is a cell line derived from a human lung adenocarcinoma carrying an activating mutation (Ex19del) in EGFRE746-A750. Both cell lines were obtained from ATCC. LC-F-12 is a cell line derived from a human lung adenocarcinoma carrying an activating point mutation in EGFRL858R and PIKC3AE545K. MR131 is an internal PDX derived from a human lung adenocarcinoma carrying an activating point mutation in EGFRL858R and PTEN D326H. CTG-2939 is a PDX derived from a human lung adenocarcinoma carrying an activating mutation (Ex19del) in EGFRE746-A750 and a deep deletion of PTEN, and CTG-2180 is a PDX derived from a human lung adenocarcinoma carrying an activating mutation (Ex19del) in EGFRL747_T751del and a PTEN frameshift at C304, both models are available from Champions Oncology.

[0249] Unless otherwise stated, all reagents were commercially available and used as received. Example 1: PIK3CA activates mutations These mutations drive resistance to osimertinib in vitro, which can be overcome by combination treatment with capasitinib.

[0250] To preclinically validate the hypothesis that PIK3CA activating mutations drive resistance to osimertinib, we used CRISPR / Cas9 technology to introduce PIK3CA in lung cancer cell line models. H1047R and PIK3CA E453Kvariants. Since the knock-in efficiency using this technology is generally low, it is expected that only a small fraction of cells will be genetically modified, mimicking the emergence of common resistance mutations in tumors. This heterogeneous cell pool was then cultured for 3 weeks under the selection pressure of osimertinib (100nM) to generate an osimertinib-resistant cell pool for downstream analysis. DNA sequencing (NGS and SANGER) of the CRISPR cell pool at the end of osimertinib selection confirmed the selective outgrowth of PIK3CAH1047R and PIK3CAE453K-positive cells, indicating that the inserted PIK3CA mutations conferred resistance to osimertinib.

[0251] PIK3CAm-induced resistance to osimertinib and its rescue by combination with capasitinib were analyzed in more detail by different experimental approaches, including:

[0252] a) Cell viability: The viability of the osimertinib-resistant PC9–PIK3CAm cell pool was compared with that of parental PC9 cells after treatment with osimertinib alone or in combination with capasitinib. 50 and can be partially rescued by co-treatment with capasitinib ( Figure 1-3 : PC9-PIK3CA treated for 6 days with osimertinib 3nM-10μM alone or in combination with capasitinib 500nM H1047R and PC9-PIK3CA E453K of determination).

[0253] b) Caspase 3 / 7 activation assay: by caspase- The 3 / 7 assay (a luminescent assay that measures intracellular caspase-3 and caspase-7 activity) was used to compare the apoptotic response induced by osimertinib in PC9–PIK3CAm cells with that in parental PC9 cells. PIK3CAm-induced resistance to osimertinib was associated with an attenuated apoptotic response that could not be restored by co-treatment with capasitinib ( Figure 4 ).

[0254] c) Clonogenicity assay: The proliferation properties of PC9-PIK3CAm cells were compared with those of parental PC9. Cells were cultured at low density (1.5x10 3 ) were plated in 6-well plates and treated with osimertinib (160 nM) alone or in combination with capasitinib (500 nM). At the end of treatment (8 days), cells were stained with crystal violet and cell density (surface %) was quantified by ImageJ. Figure 5As shown, PC9-PIK3Cam cells developed resistance to osimertinib, which could be partially rescued by combination with capasitinib.

[0255] d) Intracellular changes analyzed by WB. Protein analysis by western blotting showed that the basal levels of pAKT, pERK, and pS6 were increased in the PC9–PIK3CAm CRISPR cell pool when compared with parental PC9 cells, indicating the activation of downstream PI3K / AKT and MAPK signaling pathways in cells with osimertinib resistance. Osimertinib treatment resulted in downregulation of P-EGFR levels and MAPK signaling in both parental and PC9–PIK3CAm cells. However, in PC9–PIK3CAm cells, the levels of P-AKT and P-S6 were refractory to osimertinib treatment and could be partially downregulated in a dose-dependent manner by co-treatment with osimertinib + capasitinib ( Figure 6 , PC9 and PC9PIK3CAm cells, treated with 160 nM osimertinib alone or in combination with 100 nM-300 nM-1 μM capasitinib for 4 h).

[0256] Example 2: PTEN loss drives resistance to osimertinib in vitro, which can be reversed by combining with capasitinib Combined treatment to overcome

[0257] To preclinically validate the hypothesis that PTEN loss drives resistance to osimertinib, PTEN was depleted by CRSIPRKO in 2 NSCLC cell lines (PC9 and HCC-827). DNA sequencing and WB analysis confirmed the generated PC9 and HCC-827 PTEN KO Depletion of PTEN in (“PTEN knockout”) cell lines and resistance to osimertinib and rescue by combination with capasitinib were assessed by:

[0258] a) Cell viability: HCC-827 PTENKO and PC9 PTEN were transfected with CTG KO The sensitivity of the cell lines to osimertinib was compared with that of the parental cells (6 days of treatment with osimertinib 3 nM-10 μM). When compared with HCC-827 parental cells, two independent HCC-827 PTEN KO The cell lines exhibited resistance to osimertinib, as indicated by an increase in the EC50 of osimertinib ( Figure 7 ). When compared with parental PC9 cells, PC9 cells PTEN KO They showed similar sensitivity to osimertinib and later developed resistance after 2-3 weeks of osimertinib treatment ( Figure 8); In this PC9 model, PC9 PTEN treated with 160 nM osimertinib for 3 weeks was upregulated when compared to PC9 cells subjected to the same osimertinib exposure (PC9NTC osimertinib for 3 weeks). KO The resistance of the cells correlated with an increase in EC50.

[0259] b) Clonogenicity assay: In a long-term assay, HCC-827 PTEN treated with 160 nM osimertinib was cultured in 4% paraformaldehyde (P < 0.05). KO and PC9PTEN KO The proliferation characteristics of the cell lines were compared with those of the parental cells. 3 Cells were plated at low density in 6-well plates, treated with 160 nM osimertinib, and cell density (surface %) was calculated at the end of treatment. After 3 weeks, HCC-827 PTEN KO Cells displayed a higher cell density (20-fold), indicating that PTEN depletion led to osimertinib resistance. Co-treatment with 500 nM capasitinib partially rescued osimertinib resistance ( Fig. 9 A milder resistance phenotype was observed in the PC9 model, where PC9 PTEN was expressed when compared to parental PC9 cells. KO The cell density was only 2 times higher ( Fig.10 ).

[0260] c) Intracellular changes analyzed by WB. Protein analysis by Western blot showed that PC9PTEN was expressed in 144 cells compared to parental cells. KO and HCC-827PTEN KO Although not expected, the levels of P-AKT and P-S6 in HCC-827 PTEN KO Increased RAS-MAPK signaling was also observed in Fig.11 ). In PC9 PTEN treated with osimertinib 160nM for 3 weeks KO In cells, sustained p-S6 levels were observed ( Fig.12 For the combination of capasitinib and osimertinib, a dose-dependent downregulation of P-S6 levels was observed ( Fig.13 and 14 ).

[0261] d) Additional observations:

[0262] - In the HCC-827 in vitro model, resistance to osimertinib could be rescued by combination with capasitinib ( Fig.15 , CTG assay), consistent with the hypothesis that PTEN loss drives resistance.

[0263] - In the PC9 in vitro model, the combination of osimertinib + capasitinib can slightly sensitize cells to osimertinib. ( Fig.16 , clonogenicity assay).

[0264] Example 3: In vivo xenograft model

[0265] Additional in vivo models using patient-derived cell lines will be used to study combination activity.

[0266] a) Place PC9 PIKC3A H1047 and PC9 PIKC3A E453K The cell lines were cultured in RPMI1640 supplemented with 10% FCS and incubated at 37°C in a humidified incubator with 5% CO2. 5×10 6 PC9PIKC3A was established by subcutaneously implanting 10 cells / animal into the flank of female NOD / SCID mice. H1047 and PC9PIKC3A E453K Xenografts. All mice were older than 6 weeks at the time of cell implantation. Tumor growth was monitored twice a week by bilateral caliper measurements, and tumor volume was calculated using the formula TV (mm3) = [length (mm) × width (mm)2] × 0.5, where length and width are the longest and shortest diameters of the tumor.

[0267] PC9 PIKC3A H1047 and PC9 PIKC3A E453 It is a CRISPR engineered cell line. Fig.17 and 18 The combination of EGFR TKI and AKT inhibitor was shown to enhance the response while on treatment and delay overgrowth when treatment was stopped.

[0268] b) LC-F-12 tumor fragments from donor mice inoculated with primary human lung cancer tissue were harvested and inoculated subcutaneously into the flanks of athymic female nude mice. Tumor growth was monitored twice a week by bilateral caliper measurements, and tumor volume was calculated using the formula TV (cm3) = [length (cm) × width (cm)2] × 0.5, where length and width are the longest and shortest diameters of the tumor.

[0269] LC-F-12 is a PDX model derived from a TKI-naive patient. Fig.19 The combination of an EGFR TKI and an AKT inhibitor was shown to enhance responses while on treatment and delay overgrowth when treatment was stopped.

[0270] c) MR131 and CTG-2939 tumor fragments from donor mice inoculated with primary human lung cancer tissue were harvested and inoculated subcutaneously into the flank of female NSG mice. Tumor growth was monitored twice a week by bilateral caliper measurements and the formula TV (cm 3 )=[length (cm)×width (cm)2]×0.5 to calculate tumor volume, where length and width are the longest and shortest diameters of the tumor.

[0271] Fig. 20 showed that in MR131, a model of acquired resistance through PTEN loss, the combination of EGFR TKI and AKT inhibitor induced tumor stasis. Fig.21 We showed that in CTG-2939, a model of acquired resistance through PTEN loss, the combination exhibited superior activity to EGFR TKI monotherapy and induced tumor stasis.

[0272] d) CTG-2180 tumor fragments from donor mice inoculated with primary human lung cancer tissue were harvested and inoculated subcutaneously into the flank of athymic female nude mice. Tumor growth was monitored twice weekly by bilateral caliper measurements and the formula TV (cm 3 )=[length (cm)×width (cm) 2 ]×0.5, where length and width are the longest and shortest diameters of the tumor.

[0273] Fig. 22 We showed that in CTG-2180, a PDX model derived from a TKI-naive patient, the combination of an EGFR TKI and an AKT inhibitor induced superior tumor regression compared with EGFR TKI monotherapy.

[0274] e) PC9 PTEN-KO and HCC827 PTEN-KO cell lines were cultured in RPMI1640 supplemented with 10% FCS in a humidified incubator at 37°C and 5% CO2. 5×10 6 PC9PTEN-KO and HCC827PTEN-KO xenografts were established by subcutaneously implanting 10 cells / animal into the flank of female NOD / SCID mice and nude mice. All mice were older than 6 weeks at the time of cell implantation. Tumor growth was monitored twice weekly by bilateral caliper measurements and the formula TV (mm 3 )=[length (mm)×width (mm)2]×0.5 to calculate tumor volume, where length and width are the longest and shortest diameters of the tumor.

[0275] Fig.23We showed that in vivo, in the PTENKO CRISPR-engineered model, there was no evidence of a combination benefit between osimertinib and capasitinib. Fig.24 showed that in vivo, the degree of resistance to osimertinib in the PC9 / HCC827 PTEN KO model was very modest at best, thus limiting the opportunity to detect combinatorial benefit.

Claims

1. An EGFR TKI for use in treating cancer in a human patient, wherein the EGFR TKI is administered in combination with an AKT inhibitor.

2. The EGFR TKI for use as claimed in claim 1, wherein the EGFR TKI and the AKT inhibitor are administered separately, sequentially or simultaneously.

3. The EGFR TKI for use according to claim 1 or claim 2, wherein the EGFR TKI is a compound having formula (I): in: 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, fluorine, chlorine, methyl and cyano; R 2 is selected from the group consisting of methoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy and methyl; R 3 selected from (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]octan-2-yl, (3aR,6aR)-5-methylhexa Hydrogen-pyrrolo[3,4-b]pyrrol-1(2H)-yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 4-methylpiperazin-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-aminopropionyl]piperazin-1-yl; R 4 is selected from hydrogen, 1-piperidinylmethyl and N,N-dimethylaminomethyl; R 5 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 pharmaceutically acceptable salt thereof.

4. The EGFR TKI for use as claimed in claim 3, wherein G is selected from indol-3-yl and indazol-1-yl; R 1 is selected from hydrogen, fluorine, chlorine, 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 4 is hydrogen; 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 pharmaceutically acceptable salt thereof.

5. The EGFR TKI for use according to claim 1 or claim 2, wherein the 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, avitinib or a pharmaceutically acceptable salt thereof, afatinib or a pharmaceutically acceptable salt thereof, CX-101 or a pharmaceutically acceptable salt thereof, HS-10296 or a pharmaceutically acceptable salt thereof, BPI-7711 or a pharmaceutically acceptable salt thereof, dacomitinib or a pharmaceutically acceptable salt thereof, icotinib or a pharmaceutically acceptable salt thereof, gefitinib or a pharmaceutically acceptable salt thereof, and erlotinib or a pharmaceutically acceptable salt thereof.

6. The EGFR TKI for use as claimed in claim 5, wherein the EGFR TKI is selected from the group consisting of osimertinib or a pharmaceutically acceptable salt thereof, AZD3759 or a pharmaceutically acceptable salt thereof, afatinib or a pharmaceutically acceptable salt thereof, HS-10296 or a pharmaceutically acceptable salt thereof, and lazertinib or a pharmaceutically acceptable salt thereof. 7 . The EGFR TKI for use according to claim 6 , wherein the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof.

8. The EGFR TKI for use as claimed in any one of the preceding claims, wherein the AKT inhibitor is selected from the group consisting of: miracetide (ARQ-092) or a pharmaceutically acceptable salt thereof, BAY1125976 or a pharmaceutically acceptable salt thereof, burusetinib or a pharmaceutically acceptable salt thereof, AT7867 or a pharmaceutically acceptable salt thereof, CCT128930 or a pharmaceutically acceptable salt thereof, A-674563 or a pharmaceutically acceptable salt thereof, PHT-427 or a pharmaceutically acceptable salt thereof, Akti-1 / 2 or a pharmaceutically acceptable salt thereof, AT13148 or a pharmaceutically acceptable salt thereof, SC79 or a pharmaceutically acceptable salt thereof, capasitinib or a pharmaceutically acceptable salt thereof. salts thereof, miltefosine or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or a pharmaceutically acceptable salt thereof, sinaphthylphosphocholine or a pharmaceutically acceptable salt thereof, PBI-05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, aflosert (GSK2110183) or a pharmaceutically acceptable salt thereof, eupressor (GSK2141795) or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof, and patasert (GDC-0068) or a pharmaceutically acceptable salt thereof.

9. EGFR TKI for use as claimed in any one of the preceding claims, wherein the cancer is non-small cell lung cancer.

10. The EGFR TKI for use as claimed in claim 9, wherein the non-small cell lung cancer is EGFR mutation-positive non-small cell lung cancer.

11. The EGFR TKI for use as claimed in claim 10, wherein the EGFR mutation-positive non-small cell lung cancer comprises an activating mutation in EGFR, the activating mutation being selected from the group consisting of exon 19 deletion and L858R substitution mutation.

12. The EGFR TKI for use according to claim 10 or claim 11, wherein the EGFR mutation-positive non-small cell lung cancer comprises a T790M mutation.

13. The EGFR TKI for use according to any one of claims 1 to 11, wherein the human patient is an EGFR TKI-naive human patient.

14. The EGFR TKI for use as claimed in any one of the preceding claims, wherein the cancer comprises a PIK3CA mutation.

15. The EGFR TKI for use as claimed in any one of the preceding claims, wherein the cancer is PTEN deficient.

16. The EGFR TKI for use according to any one of claims 1 to 12, 14 or 15, wherein the human patient has had disease progression during or after previous EGFR TKI treatment.

17. The EGFR TKI for use according to claim 16, wherein the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof, and the human patient has experienced disease progression during or after previous treatment with a different EGFR TKI.

18. Use of an EGFR TKI in the preparation of a medicament for treating cancer in a human patient, wherein the EGFR TKI is administered in combination with an AKT inhibitor.

19. A method of treating cancer in a human patient in need of such treatment, the method 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.

20. A method of treating cancer in a human patient in need of such treatment, the method 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.

21. A pharmaceutical composition comprising EGFR TKI, an AKT inhibitor and a pharmaceutically acceptable excipient.

22. An AKT inhibitor for use in treating cancer in a human patient, wherein the AKT inhibitor is administered in combination with an EGFR TKI.

23. The AKT inhibitor for use in treating cancer according to claim 22, wherein the EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof.

24. The AKT inhibitor for use in treating non-small cell lung cancer according to claim 22 or claim 23, wherein the AKT inhibitor is capasitinib or a pharmaceutically acceptable salt thereof.

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