CANCER TREATMENT MODALITIES
The present disclosure provides treatment modalities, e.g., strategies, treatment methods, patient stratification methods, combinations, and compositions that are useful for the treatment of disorders, e.g., proliferative disorders, such as certain cancer. Some aspects of this disclosure provide treatment modalities, methods, strategies, compositions, combinations, and dosage forms for the treatment of cell proliferative disorders, e.g., cancers, dependent upon EZH2 (enhancer of zeste 2 polycomb repressive complex 2) function with an EZH2 inhibitor.
1 . A method, comprising administering an enhancer of a zeste homolog 2 (EZH2) inhibitor to a subject having or diagnosed with a cell proliferative disorder characterized by a cell or a population of cells that exhibits a loss of function of SMARCA2 and/or SMARCA4.
2 . A method of treating a cell proliferative disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an enhancer of a zeste homolog 2 (EZH2) inhibitor, wherein the cell proliferative disorder is characterized by a cell or a population of cells that exhibits a loss of function of SMARCA2 and/or SMARCA4.
3 . The method of any one of claim 1 or 2 , wherein the cell proliferative disorder is a cell proliferative disorder of the lung.
4 . A method of treating a cell proliferative disorder of the lung in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an enhancer of a zeste homolog 2 (EZH2) inhibitor.
5 . The method of claim 4 , wherein the cell proliferative disorder comprises or is characterized by a cell or a population of cells that exhibits a loss of function of SMARCA2 and/or a loss of function of SMARCA4.
6 . The method of any one of claim 1 , 2 or 4 , wherein the cell proliferative disorder comprises or is characterized by a cell or a population of cells that exhibits a loss of function of SMARCA2 and SMARCA4.
7 . The method of any one of claim 1 , 2 or 4 , wherein the cell proliferative disorder is characterized by a stem-, stem-like, or progenitor cell of origin.
8 . The method of any one of claim 1 , 2 or 4 , wherein the cell proliferative disorder of the lung is characterized by a malignant growth or lesion in the lung.
9 . The method of claim 8 , wherein the malignant growth or lesion is a primary lesion.
10 . The method of claims 8 , wherein the malignant growth or lesion is, or is characterized by, a secondary or metastatic lesion.
11 . The method of claim 8 , wherein the malignant growth is a malignant lung neoplasm, a carcinoma, or a carcinoid tumor.
12 . The method of any one of claim 1 , 2 or 4 , wherein the cell proliferative disorder of the lung is asbestos-induced hyperplasia, squamous metaplasia, and benign reactive mesothelial metaplasia.
13 . The method of any one of claim 1 , 2 or 4 , wherein the cell proliferative disorder of the lung is lung cancer.
14 . The method of claim 13 , wherein the lung cancer is small cell lung cancer.
15 . The method of claim 13 , wherein the lung cancer is non-small cell lung cancer.
16 . The method of claim 13 , wherein the lung cancer is a squamous cell carcinoma.
17 . The method of claim 13 , wherein the lung cancer is an adenocarcinoma.
18 . The method of claim 13 , wherein the lung cancer is a small cell carcinoma.
19 . The method of claim 13 , wherein the lung cancer is a large cell carcinoma.
20 . The method of claim 13 , wherein the lung cancer is an adenosquamous cell carcinoma.
21 . The method of claim 13 , wherein the lung cancer is mesothelioma.
22 . The method of any one of claim 1 , 2 , or 4 , wherein the cell proliferative disease is characterized by a primary tumor, wherein the primary tumor
(A) exhibits SMARCA2/SMARCA4 dual loss; and
(B) is poorly differentiated and/or exhibits epithelial to mesenchymal transition (EMT) features.
23 . The method of claim 22 , wherein the primary tumor exhibits low E-cadherin and high vimentin expression levels.
24 . The method of any one of claim 1 , 2 or 4 , wherein the subject has been or is being administered an additional therapeutic agent concurrently or in temporal proximity with the administration of the EZH2 inhibitor.
25 . The method of claim 24 , wherein the additional therapeutic agent is a standard-of-care agent.
26 . The method of claim 25 , wherein the additional agent is or comprises an agent listed in Schematic 1, or is or comprises a combination of two or more agents listed in Schematic 1.
27 . The method of claim 24 , wherein the additional therapeutic agent is an immune checkpoint inhibitor.
28 . The method of claim 27 , wherein the immune checkpoint inhibitor is a CTLA4 inhibitor, a PD-1 inhibitor and/or a PD-L1 inhibitor, a LAG3 inhibitor, a B7-H3 inhibitor, or a Tim3 inhibitor.
29 . The method of claim 28 , wherein the immune checkpoint inhibitor comprises Ipilimumab, Ticilimumab, AGEN-1884, Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab, Avelumab, BMS-936559, AMP-224, MEDI-0680, TSR-042, BGB-108, STI-1014, KY-1003, ALN-PDL, BGB-A317, KD-033, REGN-2810, PDR-001, SHR-1210, MGD-013, PF-06801591, CX-072, IMP-731, LAG-525, BMS-986016, GSK-2831781, Enoblituzumab, 1241-8H9, DS-5573, MBG-453, or a combination thereof.
30 . The method of any claims 24 , wherein the EZH2 inhibitor and the additional therapeutic agent are administered sequentially to the subject.
31 . The method of claim 24 , wherein the EZH2 inhibitor and the additional therapeutic agent are administered via different administration routes and at different intervals.
32 . The method of any one of claim 1 , 2 or 4 , wherein the EZH2 inhibitor is administered orally twice a day.
33 . The method of any one of claim 1 , 2 or 4 , wherein the method further comprises detecting SMARCA2 and/or SMARCA4 protein expression and/or a function of a SMARCA2 and/or of a SMARCA4 protein.
34 . The method of claim 33 , wherein the expression and/or function of the SMARCA2 and/or the SMARCA4 protein is evaluated by a method comprising:
(a) obtaining a biological sample from the subject;
(b) contacting the biological sample or a portion thereof with an antibody that specifically binds SMARCA2 or SMARCA4; and
(c) detecting an amount of the antibody that is bound to SMARCA2 or SMARCA4.
35 . The method of any one of claim 1 , 2 or 4 , wherein the method further comprises detecting a genomic mutation in the gene encoding the SMARCA2 and/or the gene encoding the SMARCA4 protein in a biological sample obtained from the subject.
36 . The method of claim 35 , wherein the genomic mutation is detected by a method comprising:
(a) obtaining a biological sample from the subject;
(b) sequencing at least one DNA sequence encoding a SMARCA2 protein or a portion thereof, and/or at least one DNA sequence encoding a SMARCA4 protein or a portion thereof, in the biological sample; and
(c) determining if the at least one DNA sequence encoding a SMARCA2 protein or a portion thereof, and/or the at least one DNA sequence encoding a SMARCA4 protein or a portion thereof, comprises a mutation affecting the expression and/or function of the SMARCA2 protein or the SMARCA4 protein.
37 . The method of any one of claim 1 or 2 , wherein the EZH2 inhibitor inhibits tri-methylation of lysine 27 of histone 3 (H3K27).
38 . A method, comprising detecting a SMARCA2 and/or a SMARCA4 loss of function in a sample obtained from a subject.
39 . The method of claim 38 , wherein the subject has cancer.
40 . The method of any one of claim 38 or 39 , wherein the method further comprises administering an EZH2 inhibitor to the subject, if a SMARCA2 and/or SMARCA4 loss of function is detected in the subject.
41 . The method of claim 40 , wherein the SMARCA2 loss of function is not associated with a genomic mutation in a gene encoding SMARCA2 protein, and/or wherein the SMARCA4 loss of function is associated with a genomic mutation in a gene encoding SMARCA4.
42 . The method of claim 38 , wherein the subject has NSCLC.
43 . The method of any one of claim 1 , 2 , or 4 , wherein the EZH2 inhibitor is
or a pharmaceutically acceptable salt thereof.
44 . The method of any one of claim 1 , 2 , or 4 , wherein the EZH2 inhibitor is
a stereoisomer, a pharmaceutically acceptable salt and/or a solvate thereof.
45 . The method of any one of claim 1 , 2 , or 4 , wherein the EZH2 inhibitor is
or a pharmaceutically acceptable salt thereof.
46 . The method of any one of claim 1 , 2 , or 4 , wherein the EZH2 inhibitor is
a stereoisomer, a pharmaceutical acceptable salt and/or a solvate thereof.
47 . The method of any one of claim 1 , 2 , or 4 , wherein the EZH2 inhibitor is
a stereoisomer, a pharmaceutically acceptable salt and/or a solvate thereof.
48 . The method of any one of claim 1 , 2 , or 4 , wherein the EZH2 inhibitor is
a stereoisomer, a pharmaceutically acceptable salt and/or a solvate thereof.
49 . The method of any one of claim 1 , 2 , or 4 , wherein the EZH2 inhibitor is administered orally.
50 . The method of any one of claims 1 , 2 , or 4 , wherein the EZH2 inhibitor is formulated as an oral tablet.
51 . The method of any one of claim 1 , 2 , or 4 , wherein the EZH2 inhibitor is administered at a dose of between 10 mg/kg/day and 1600 mg/kg/day.
52 . The method of any one of claim 1 , 2 , or 4 , wherein the EZH2 inhibitor is administered at a dose of about 100, 200, 400, 800, or 1600 mg.
53 . The method of any one of claim 1 , 2 , or 4 , wherein the EZH2 inhibitor is administered at a dose of about 800 mg.
54 . The method of any one of claim 1 , 2 , or 4 , wherein the EZH2 inhibitor is administered twice per day (BID).
55 . Use of an enhancer of a zeste homolog 2 (EZH2) inhibitor for treating a cell proliferative disorder in a subject in need thereof, the use comprising administering to the subject a therapeutically effective amount of an enhancer of a zeste homolog 2 (EZH2.) inhibitor, wherein the cell proliferative disorder is characterized by a cell or a population of cells that exhibits a loss of function of SMARCA2 and/or SMARCA4.
56 . The use of claim 55 , wherein the cell proliferative disorder is a cell proliferative disorder of the lung.
57 . Use of an enhancer of zeste homolog 2 (EZH2) inhibitor, for treating a cell proliferative disorder of the lung in a subject in need thereof, the use comprising administering to the subject a therapeutically effective amount of the enhancer of a zeste homolog 2 (EZH2) inhibitor.
58 . The use of claim 57 , wherein the cell proliferative disorder comprises or is characterized by a cell or a population of cells that exhibits a loss of function of SMARCA2 and/or a loss of function of SMARCA4.
59 . The use of any one of claims 55 - 58 , wherein the cell proliferative disorder comprises or is characterized by a cell or a population of cells that exhibits a loss of function of SMARCA2 and SMARCA4.
60 . The use of any one of claims 55 - 59 , wherein the cell proliferative disorder is characterized by a stem-, stem-like, or progenitor cell of origin.
61 . The use of any one of claims 55 - 60 , wherein the cell proliferative disorder of the lung is characterized by a malignant growth or lesion in the lung.
62 . The use of any one of claims 55 - 61 , wherein the malignant growth or lesion is a primary lesion.
63 . The use of any one of claims 55 - 62 , wherein the malignant growth or lesion is, or is characterized by, a secondary or metastatic lesion.
64 . The use of any one of claims 55 - 63 , wherein the malignant growth is a malignant lung neoplasm, a carcinoma, or a carcinoid tumor.
65 . The use of any one of claims 55 - 64 , wherein the cell proliferative disorder of the lung is asbestos-induced hyperplasia, squamous metaplasia, and benign reactive mesothelial metaplasia.
66 . The use of any one of claims 55 - 65 , wherein the cell proliferative disorder of the lung is lung cancer.
67 . The use of claim 66 , wherein the lung cancer is small cell lung cancer.
68 . The use of claim 66 , wherein the lung cancer is non-small cell lung cancer.
69 . The use of claim 66 , wherein the lung cancer is a squamous cell carcinoma.
70 . The use of claim 66 , wherein the lung cancer is an adenocarcinoma.
71 . The use of claim 66 , wherein the lung cancer is a small cell carcinoma.
72 . The use of claim 66 , wherein the lung cancer is a large cell carcinoma.
73 . The use of claim 66 , wherein the lung cancer is an adenosquamous cell carcinoma.
74 . The use of claim 66 , wherein the lung cancer is mesothelioma.
75 . The use of any one of claims 55 - 74 , wherein the cell proliferative disease is characterized by a primary tumor, wherein the primary tumor
(A) exhibits SMARCA2/SMARCA4 dual loss; and
(B) is poorly differentiated and/or exhibits epithelial to mesenchymal transition (EMT) features.
76 . The use of claim 75 , wherein the primary tumor exhibits low E-cadherin and high vimentin expression levels.
77 . The use of any one of claims 55 - 76 , wherein the subject has been or is being administered an additional therapeutic agent concurrently or in temporal proximity with the administration of the EZH2 inhibitor.
78 . The use of claim 77 , wherein the additional therapeutic agent is a standard-of-care agent.
79 . The use of claim 78 , wherein the additional agent is or comprises an agent listed in Schematic 1, or is or comprises a combination of two or more agents listed in Schematic 1.
80 . The use of claim 79 , wherein the additional therapeutic agent is an immune checkpoint inhibitor.
81 . The use of claim 80 , wherein the immune checkpoint inhibitor is a CTLA4 inhibitor, a PD-1 inhibitor and/or a PD-L1 inhibitor, a LAG3 inhibitor, a B7-H3 inhibitor, or a Tim3 inhibitor.
82 . The use of claim 81 , wherein the immune checkpoint inhibitor comprises Ipilimumab, Ticilimumab, AGEN-1884, Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab, Avelumab, BMS-936559, AMP-224, MEDI-0680, TSR-042, BGB-108, STI-1014, KY-1003, ALN-PDL, BGB-A317, KD-033, REGN-2810, PDR-001, SHR-1210, MGD-013, PF-06801591, CX-072, IMP-731, LAG-525, BMS-986016, GSK-2831781 Enoblituzumab, 1241-8H9, DS-5573, MBG-453, or a combination thereof.
83 . The use of any one of claims 77 - 82 , wherein the EZH2 inhibitor and the additional therapeutic agent are administered sequentially to the subject.
84 . The use of any one of claims 77 - 83 , wherein the EZH2 inhibitor and the additional therapeutic agent are administered via different administration routes and at different intervals.
85 . The use of any one of claims 55 - 84 , wherein the EZH2 inhibitor is administered orally twice a day.
86 . The use of any one of claims 55 - 85 , wherein the use further comprises detecting SMARCA2 and/or SMARCA4 protein expression and/or a function of a SMARCA2 and/or of a SMARCA4 protein.
87 . The use of claim 86 , wherein the expression and/or function of the SMARCA2 and/or the SMARCA4 protein is evaluated by the steps comprising:
(a) obtaining a biological sample from the subject;
(b) contacting the biological sample or a portion thereof with an antibody that specifically binds SMARCA2 or SMARCA4; and
(c) detecting an amount of the antibody that is bound to SMARCA2 or SMARCA4.
88 . The use of any one of claims 55 - 87 , wherein the use further comprises detecting a genomic mutation in the gene encoding the SMARCA2 and/or the gene encoding the SMARCA4 protein in a biological sample obtained from the subject.
89 . The use of claim 88 , wherein the genomic mutation is detected by the steps comprising:
(a) obtaining a biological sample from the subject;
(b) sequencing at least one DNA sequence encoding a SMARCA2 protein or a portion thereof, and/or at least one DNA sequence encoding a SMARCA4 protein or a portion thereof, in the biological sample; and
(c) determining if the at least one DNA sequence encoding a SMARCA2 protein or a portion thereof, and/or the at least one DNA sequence encoding a SMARCA4 protein or a portion thereof, comprises a mutation affecting the expression and/or function of the SMARCA2 protein or the SMARCA4 protein.
90 . The use of claim 55 , wherein the EZH2 inhibitor inhibits tri-methylation of lysine 27 of histone 3 (H3K27).
91 . The use of any one of claims 88 - 89 , wherein the use further comprises detecting a SMARCA2 and/or a SMARCA4 loss of function in a sample obtained from a subject.
92 . The use of claim 91 , wherein the SMARCA2 loss of function is not associated with a genomic mutation in a gene encoding SMARCA2 protein, and/or wherein the SMARCA4 loss of function is associated with a genomic mutation in a gene encoding SMARCA4.
93 . The use of any one of claims 91 - 92 , wherein the subject has NSCLC.
94 . The use of any one of claims 55 - 93 , wherein the EZH2 inhibitor is
or a pharmaceutically acceptable salt thereof.
95 . The use of any one of claims 55 - 93 , wherein the EZH2 inhibitor is
a stereoisomer, a pharmaceutically acceptable salt and/or a solvate thereof.
96 . The use of any one of claims 55 - 93 , wherein the EZH2 inhibitor is
or a pharmaceutically acceptable salt thereof.
97 . The use of any one of claims 55 - 93 , wherein the EZH2 inhibitor is
a stereoisomer, a pharmaceutically acceptable salt and/or a solvate thereof.
98 . The use of any one of claims 55 - 93 , wherein the EZH2 inhibitor is
a stereoisomer, a pharmaceutically acceptable salt and/or a solvate thereof.
99 . The use of any one of claims 55 - 93 , wherein the EZH2 inhibitor is
a stereoisomer, a pharmaceutically acceptable salt and/or a solvate thereof.
100 . The use of any one of claims 55 - 93 , wherein the EZH2 inhibitor is administered orally.
101 . The use of any one of claims 55 - 93 , wherein the EZH2 inhibitor is formulated as an oral tablet.
102 . The use of any one of claims 55 - 93 , wherein the EZH2 inhibitor is administered at a dose of between 10 mg/kg/day and 1600 mg/kg/day.
103 . The use of any one of claims 55 - 93 , wherein the EZH2 inhibitor is administered at a dose of about 100, 200, 400, 800, or 1600 mg.
104 . The use of any one of claims 55 - 93 , wherein the EZH2 inhibitor is administered at a dose of about 800 mg.
105 . The use of any one of claims 55 - 93 , wherein the EZH2 inhibitor is administered twice per day (BID).