METHODS OF TREATING CANCER IN BIOMARKER-IDENTIFIED PATIENTS WITH NON-COVALENT INHIBITORS OF CYCLIN-DEPENDENT KINASE 7 (CDK7)
The present invention relates to methods of identifying patients suffering from various types of cancer who are more likely to respond to treatment with a CDK7 inhibitor conforming to structural Formula (I), (Ia), a species thereof, or a specified form thereof (as described herein), either when administered or used alone or in combination with a second therapeutic agent (e.g., another anti-cancer therapy). Patients are identified based on one or more features (e.g., gene copy number or expression level) of certain biomarkers (e.g., RB1 or another member of the E2F pathway). In addition, the present invention relates to methods of treating an identified patient with a compound conforming to structural Formula (I), (Ia), a species thereof, or a specified form thereof, either alone or in combination with a second therapeutic agent. In another aspect, the present invention features kits including instructions for treating a patient identified as described herein.
1 . A method of treating a selected patient, the method comprising administering a therapeutically effective amount of a compound of structural Formula (I):
or a pharmaceutically acceptable salt thereof, wherein the compound or the pharmaceutically acceptable salt thereof is optionally within a pharmaceutical composition;
R 1 is methyl or ethyl;
R 2 is methyl or ethyl;
R 3 is 5-methylpiperidin-3-yl, 5,5-dimethylpiperidin-3-yl, 6-methylpiperdin-3-yl, or 6,6-dimethylpiperidin-3-yl, wherein one or more hydrogen atoms in R 3 is optionally replaced by deuterium;
R 4 is —CF 3 or chloro;
and the selected patient has been determined to have a cancer in which
(a) a gene selected from RB1, RBL1, RBL2, CDKN2A, CDKN2B, CDKN2C, CDKN2D, CDKN1A, CDKN1B, CDKN1C, and FBWX7 is mutated, is genetically deleted, contains an epigenetic alteration, is translocated, is transcribed at a level equal to or below a pre-determined threshold, or encodes a protein that is translated at a level equal to or below a pre-determined threshold or has decreased activity relative to a reference standard;
(b) a gene selected from E2F1, E2F2, E2F3, E2F4, E2F5, E2F6, E2F7, E2F8, CDK1, CDK2, CDK4, CDK6, CCNA1, CCNB1, CCND1, CCND2, CCND3, CCNE1, CCNE2, and BRAF is mutated, is genetically gained or amplified, contains an epigenetic alteration, is translocated, transcribed at a level equal to or above a pre-determined threshold, or encodes a protein that is translated at a level equal to or above a pre-determined threshold or has increased activity relative to a reference standard; or
(c) the gene Bcl2-like 1 is mutated, contains an epigenetic alteration, is translocated, is transcribed at a level equal to or below a pre-determined threshold, or encodes a BCL-xL protein that is translated at a level equal to or below a pre-determined threshold or has decreased activity relative to a reference standard.
2 . The method of claim 1 , wherein (i) R 1 is methyl and R 2 is methyl or (ii) R 1 is methyl and R 2 is ethyl.
3 . The method of claim 1 , wherein (i) R 1 is ethyl and R 2 is ethyl or (ii) R 4 is —CF 3 .
4 . The method of claim 1 , wherein R 4 is chloro.
5 . The method of claim 1 , wherein R 3 is 5-methylpiperidin-3-yl.
6 . The method of claim 1 , wherein R 3 is 5,5-dimethylpiperidin-3-yl.
7 . The method of claim 1 , wherein R 3 is 6-methylpiperdin-3-yl.
8 . The method of claim 1 , wherein R 3 is 6,6-dimethylpiperidin-3-yl.
9 . The method of claim 1 , wherein the compound has structural Formula (Ia):
is a pharmaceutically acceptable salt thereof, wherein R 3 is
10 .- 12 . (canceled)
13 . The method of claim 9 , wherein the compound is:
or is a pharmaceutically acceptable salt of any one of the foregoing compounds.
14 . The method of claim 13 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
15 .- 18 . (canceled)
19 . The method of claim 1 , wherein the cancer is a blood cancer, a breast cancer, Ewing's sarcoma, fallopian tube cancer, a GI tract cancer, a glioma, a lung cancer, melanoma, an osteosarcoma, an ovarian cancer, a pancreatic cancer, a primary peritoneal cancer, prostate cancer, retinoblastoma, or a squamous cell cancer of the head or neck.
20 . (canceled)
21 . The method of claim 19 , wherein the patient has undergone, is presently undergoing, or is prescribed treatment with a Bcl-2 inhibitor.
22 . The method of claim 21 , wherein the Bcl-2 inhibitor is venetoclax and/or wherein the patient has a breast cancer, a blood cancer, an ovarian cancer, or a lung cancer.
23 . The method of claim 19 , wherein the patient has been determined to have a cancer in which
(a) RB1 or CDKN2A is mutated, contains an epigenetic alteration, is translocated, is transcribed at a level equal to or below a pre-determined threshold, or encodes a protein that is translated at a level equal to or below a pre-determined threshold or has decreased activity relative to a reference standard; and/or
(b) CDK6, CCND2, or CCNE1 is mutated, has a copy number alteration, contains an epigenetic alteration, is translocated, transcribed at a level equal to or above a pre-determined threshold, or encodes a protein that is translated at a level equal to or above a pre-determined threshold or has increased activity relative to a reference standard.
24 . The method of claim 19 , wherein the patient has undergone, is presently undergoing, or is prescribed treatment with a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a PARP inhibitor, or a platinum-based therapeutic agent.
25 . The method of claim 24 , wherein the patient has undergone, is presently undergoing, or is prescribed treatment with a SERM or SERD and has an HR+ breast cancer; the patient has undergone, is presently undergoing, or is prescribed treatment with a PARP inhibitor and has breast cancer, fallopian tube cancer, a glioma, ovarian cancer, or primary peritoneal cancer; or the patient has undergone, is presently undergoing, or is prescribed treatment with a platinum-based therapeutic agent and has an ovarian cancer.
26 . The method of claim 19 , wherein the patient has undergone, is presently undergoing, or is prescribed treatment with a BET inhibitor with a CDK4/6 inhibitor; with a FLT3 inhibitor; or with a MEK inhibitor.
27 . The method of claim 26 , wherein the patient who has undergone, is presently undergoing, or is prescribed treatment with the CDK4/6 inhibitor has a breast cancer, a pancreatic cancer, or a squamous cell cancer of the head or neck; the patient who has undergone, is presently undergoing, or is prescribed treatment with the FLT3 inhibitor has a blood cancer; or the patient who has undergone, is presently undergoing, or is prescribed treatment with the BET inhibitor has a breast cancer, a blood cancer, Ewing's sarcoma, or an osteosarcoma.
28 . The method of claim 1 , wherein the patient has undergone, is presently undergoing, or is prescribed treatment with a second anti-cancer agent.
29 . The method of claim 28 , wherein the second anti-cancer agent is a Bcl-2 inhibitor a CDK9 inhibitor; a hormone receptor degradation agent; a Flt3 (FMS-like tyrosine kinase 3) inhibitor; a PARP inhibitor; a BET inhibitor; a platinum-based therapeutic agent; a CDK4/6 inhibitor; a MEK inhibitor; or a phosphoinositide 3-kinase (PI3 kinase) inhibitor.
30 . The method of claim 29 , wherein the Bcl-2 inhibitor is venetoclax, the PARP inhibitor is olaparib or niraparib, the platinum-based anti-cancer agent is carboplatin or oxaliplatin, the CDK4/6 inhibitor is palbociclib, ribociclib, abemaciclib, or trilaciclib, and the hormone receptor degradation agent is fulvestrant.