JPWO2020118213A5 - - Google Patents

Claims (21)

A pharmaceutical composition comprising elasestrant or a pharmaceutically acceptable salt or solvate thereof for use in a method of inhibiting and degrading CDK4/6 inhibitor-resistant estrogen receptor alpha-positive cancer in a subject. A pharmaceutical composition, wherein the method comprises administering to the subject a therapeutically effective amount of elasestrant or a pharmaceutically acceptable salt or solvate thereof . 2. The pharmaceutical composition of claim 1, wherein the CDK4/6 inhibitor-resistant estrogen receptor alpha-positive cancer is resistant to or progresses against palbociclib, ribociclib, abemaciclib, or a combination thereof . 2. The pharmaceutical composition of claim 1, wherein the CDK4/6 inhibitor-resistant estrogen receptor alpha-positive cancer is resistant to or progresses to palbociclib. 2. The pharmaceutical composition of claim 1, wherein the CDK4/6 inhibitor-resistant estrogen receptor alpha-positive cancer is resistant to or progresses to ribociclib. 2. The pharmaceutical composition of claim 1, wherein the CDK4/6 inhibitor-resistant estrogen receptor alpha-positive cancer is resistant to or progresses to abemaciclib. CDK4/6 inhibitor-resistant estrogen receptor alpha-positive cancer is D538G, Y537X ₁ , L536X ₂ , P535H, V534E, S463P, V392I, E380Q and combinations thereof (where X ₁ is S, N or C; X ₂ is R or Q ). 7. The pharmaceutical composition of claim 6, wherein the mutation is Y537S. 7. The pharmaceutical composition of Claim 6, wherein the mutation is D538G. CDK4/6 inhibitor-resistant estrogen receptor alpha-positive cancer is further resistant to or progresses to a drug selected from the group consisting of antiestrogens, aromatase inhibitors and combinations thereof. Item 9. The pharmaceutical composition according to any one of items 1 to 8. The pharmaceutical composition according to any one of claims 1 to 9, wherein the CDK4/6 inhibitor-resistant estrogen receptor α-positive cancer is selected from the group consisting of breast cancer, uterine cancer, ovarian cancer, breast cancer brain metastasis and pituitary cancer. The pharmaceutical composition according to any one of claims 1 to 10, wherein the CDK4/6 inhibitor-resistant estrogen receptor α-positive cancer is advanced or metastatic breast cancer. The pharmaceutical composition according to any one of claims 1 to 10, wherein the CDK4/6 inhibitor-resistant estrogen receptor α-positive cancer is breast cancer. The pharmaceutical composition according to any one of claims 1 to 12, wherein the subject is a postmenopausal woman. The pharmaceutical composition according to any of claims 1-12, wherein the subject is a premenopausal woman. 13. The subject of any of claims 1-12, wherein the subject is a post-menopausal woman who has relapsed or progressed after prior treatment with a selective estrogen receptor modulator (SERM) and/or an aromatase inhibitor (AI). pharmaceutical composition . 16. The pharmaceutical composition of any of claims 1-15, wherein elasestrant is administered to the subject at a dose of about 200 mg/day to about 500 mg/day. 17. The pharmaceutical composition of any of claims 1-16, wherein elasestrant is administered to the subject at a dose of about 200 mg/day, about 300 mg/day, about 400 mg/day or about 500 mg/day. 16. The pharmaceutical composition of any of claims 1-15, wherein elasestrant is administered to the subject at a dose that is the maximum tolerated dose for the subject. ABL1, AKT1, AKT2, ALK, APC, AR, ARID1A, ASXL1, ATM, AURKA, BAP, BAP1, BCL2L11, BCR, BRAF, BRCA1, BRCA2, CCND1, CCND2, CCND3, CCNE1, CDH1, CDK4, CDK6, CDK8, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CEBPA, CTNNB1, DDR2, DNMT3A, E2F3, EGFR, EML4, EPHB2, ERBB2, ERBB3, ESR1, EWSR1, FBXW7, FGF4, FGFR1, FGFR2, FGFR3, FLT3, FRS2, HIF1A, HRAS, IDH1, IDH2, IGF1R, JAK2, KDM6A, KDR, KIF5B, KIT, KRAS, LRP1B, MAP2K1, MAP2K4, MCL1, MDM2, MDM4, MET, MGMT, MLL, MPL, MSH6, MTOR, MYC, NF1, NF2, NKX2-1, NOTCH1, NPM, NRAS, PDGFRA, PIK3CA, PIK3R1, PML, PTEN, PTPRD, RARA, RB1, RET, RICTOR, ROS1, RPTOR, RUNX1, SMAD4, SMARCA4, SOX2, STK11, TET2, TP53, The pharmaceutical composition of any of claims 1-18, further comprising identifying the subject for treatment by measuring increased expression of one or more genes selected from TSC1, TSC2 and VHL. . 20. The pharmaceutical composition according to claim 19, wherein the one or more genes are selected from AKT1, AKT2, BRAF, CDK4, CDK6, PIK3CA, PIK3R1 and MTOR. 3. The ratio (T/P) of the concentration of elasestrant or a salt or solvate thereof in the tumor to the concentration of elasestrant or a salt or solvate thereof in the plasma after administration is at least about 15. The pharmaceutical composition according to any one of 1 to 20.