Methods and Dosing Regimens Comprising CDK2 and CDK4 Inhibitors for Treating Cancer - Patent application

Abstract

The present disclosure relates to a combination therapy for use in treating cancer, comprising a CDK2 inhibitor of Formula (I) and a selective CDK4 inhibitor of Formula (II), each as further described herein, optionally further in combination with an additional anti-cancer agent.

Description

[Technical field]

[0001] The present disclosure relates to methods and combination therapies useful for treating cancer in a subject in need thereof. In particular, the present disclosure relates to a method for treating cancer in a subject in need thereof, comprising administering to a subject a cyclin-dependent kinase 2 (CDK2) inhibitor, such as (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentylpropan-2-ylcarbamate (hereinafter PF-07104091) or its monohydrate, in combination with 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1H-pyrazol-5 ... The present disclosure relates to methods and combinations comprising in combination with a selective cyclin-dependent kinase 4 (CDK4) inhibitor such as -(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (hereinafter PF-07220060) or a pharma- ceutically acceptable salt thereof, where the combination may be further combined with an additional anti-cancer agent such as an endocrine therapy agent. The present disclosure also relates to associated dosage regimens, uses and pharmaceutical compositions. [Background technology]

[0002] Cyclin-dependent kinases (CDKs) are important cellular enzymes that perform essential functions in regulating eukaryotic cell division and proliferation. CDK inhibitors may be useful in the treatment of proliferative disorders, including cancer.

[0003] Overexpression of CDK2 is associated with dysregulation of the cell cycle. The cyclin E / CDK2 complex plays a key role in regulating the G1 / S transition, histone biosynthesis and centrosome duplication. Progressive phosphorylation of retinoblasts (RBs) by cyclin D / Cdk4 / 6 and cyclin E / Cdk2 releases the G1 transcription factor E2F and promotes S-phase entry. Activation of cyclin A / CDK2 during early S-phase promotes phosphorylation of endogenous substrates that allow DNA replication and inactivation of E2F for S-phase completion (Asghar et al., The history and future of targeting cyclin-dependent kinases in cancer therapy, Nat. Rev. Drug. Discov. 2015;14(2):130-146).

[0004] Cyclin E, the regulatory cyclin for CDK2, is frequently overexpressed in cancer. Cyclin E amplification or overexpression has long been associated with poor outcome in breast cancer (Keyomarsi et al., Cyclin E and survival in patients with breast cancer. N Engl J Med. (2002) 347:1566-75). Cyclin E2 (CCNE2) overexpression is associated with endocrine resistance in breast cancer cells, and CDK2 inhibition has been reported to restore tamoxifen resistance and sensitivity to tamoxifen or CDK4 inhibitors in cells overexpressing CCNE2 (Caldon et al., Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells. Mol. Cancer Ther. (2012) 11:1488-99; Herrera-Abreu et al., Early Adaptation and Acquired Resistance to CDK4 / 6 Inhibition in Estrogen Receptor-Positive Breast Cancer, Cancer Res. (2016) 76:2301-2313). Cyclin E amplification also reportedly contributes to trastuzumab resistance in human epidermal growth factor receptor 2-positive (HER2+) breast cancer (Scaltriti et al., Cyclin E amplification / overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients, Proc Natl Acad Sci. (2011) 108:3761-6).Cyclin E overexpression has also been reported to play a role in basal-like triple-negative breast cancer (TNBC) as well as inflammatory breast cancer (Elsawaf and Sinn, Triple Negative Breast Cancer: Clinical and Histological Correlations, Breast Care (2011) 6:273-278; Alexander et al., Cyclin E overexpression as a biomarker for combination treatment strategies in inflammatory breast cancer, Oncotarget (2017) 8:14897-14911).

[0005] High CCNE1 mRNA expression was found to be associated with relative resistance to palbociclib in gene expression analyses from the PALOMA-3 trial, suggesting a role for CDK2 inhibition in reducing or overcoming resistance to CDK4 / 6 inhibition (Turner et al., Cyclin E1 Expression and Palbociclib Efficacy in Previously Treated Hormone Receptor-Positive Metastatic Breast Cancer, J. Clin. Oncol. (2019) 37:1169-1178). Amplification or overexpression of Cyclin E1 (CCNE1) is also associated with poor outcome in ovarian, gastric, endometrial, and other cancers (Nakayama et al., Gene amplification CCNE1 is related to poor survival and potential therapeutic target in ovarian cancer, Cancer (2010) 116:2621-34; Etemadmoghadam et al., Resistance to CDK2 Inhibitors Is Associated with Selection of Polyploid Cells in CCNE1-Amplified Ovarian Cancer, Clin Cancer Res (2013) 19:5960-71; Au-Yeung et al., Selective Targeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer by Cyclin-Dependent Kinase 2 and AKT Inhibition, Clin. Cancer Res.(2017)23:1862~1874;Ayhan et al., CCNE1 copy-number gain and overexpression identify ovarian clear cell carcinoma with a poor prognosis, Modern Pathology(2017)30:297~303;Ooi et al., Gene amplification of CCNE1,CCND1,and CDK6 in gastric cancers detected by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization, Hum Pathol. (2017) 61:58~67; Noske et al., Detection of CCNE1 / URI(19q12) amplification by in situ hybridization is common in high grade and type II endometrial cancer, Oncotarget (2017) 8:14794~14805). .

[0006] CDK4 and CDK6 are D-type cyclins and p16 INK4a It is a key regulator of cell cycle progression at the G1-S checkpoint, which is controlled by INK4 endogenous CDK inhibitors such as (CDKN2A). Dysregulation of the cyclin D-CDK4 / 6-INK4-retinoblastoma (Rb) pathway has been reported to be associated with the development of endocrine therapy resistance.

[0007] CDK4 / 6 inhibition has emerged as a promising strategy for cancer therapy, particularly for the treatment of endocrine-resistant breast cancer (BC) (Rani, A. et al., Endocrine Resistance in Hormone Receptor Positive Breast Cancer-From Mechanism to Therapy. Front Endocrinol (Lausanne) 10:245, 2019).

[0008] CDK4 / 6 inhibitors (e.g., palbociclib, abemaciclib, ribociclib) have significantly improved progression-free survival and / or overall survival for patients with HR-positive / HER2-negative advanced or metastatic breast cancer when administered in combination with endocrine therapy (Spring, LM et al., Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future. Lancet, 395, 817-827, 2020). However, CDK4 / 6 inhibitors have been associated with dose-limiting hematologic toxicities, primarily neutropenia and gastrointestinal toxicity. As with other kinase inhibitors, the efficacy of CDK4 / 6 inhibitors may be limited over time by the development of primary or acquired resistance.

[0009] Emerging data suggest that cyclin D3-CDK6 may be involved in the observed hematologic toxicity (Malumbres et al., Mammalian Cells Cycle without the D-type Cyclin-Dependent Kinases Cdk4 and Cdk6 (2004) Cell 118(4):493-504; Sicinska et al., Essential Role for Cyclin D3 in Granulocyte Colony-Stimulating Factor-Driven Expansion of Neutrophil Granulocytes (2006), Mol. Cell Biol 26(21):8052-8060; Cooper et al., A unique function for Cyclin D3 in early B cell development (2006), Nat. Immunol. 5(7):489-497). CDK4 has been identified as the sole oncogene driver in many breast cancers. Thus, CDK4 selective inhibitors may offer an improved safety profile or enhanced overall efficacy with the potential for higher and / or continuous dosing compared to dual CDK4 / 6 inhibitors.

[0010] The compound (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentylpropan-2-ylcarbamate (hereinafter PF-07104091) has the structure:

[0011] [ka] It is a potent and selective inhibitor of CDK2.

[0012] PF-07104091 (Pfizer Inc.) is currently in clinical development for the treatment of certain cancers. The preparation of PF-07104091 is disclosed in International Patent Publication No. WO2020 / 157652 and U.S. Patent No. 11,014,911, the contents of each of which are incorporated herein by reference in their entirety. PF-07104091 is also named (1R,3S)-3-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-5-yl)cyclopentyl isopropyl carbamate as produced by ChemDraw 20.1.1.

[0013] The compound 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (hereinafter PF-07220060) has the structure:

[0014] [ka] a potent and selective inhibitor of CDK4, or a pharma- ceutically acceptable salt thereof.

[0015] PF-07220060 (Pfizer Inc.) is currently in clinical development for the treatment of certain cancers. The preparation of PF-07220060 is disclosed in International Patent Publication No. WO2019 / 207463 and U.S. Patent No. 10,766,884, the contents of each of which are incorporated herein by reference in their entirety. PF-07220060 is also known as (3S,4R)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol as produced by ChemDraw 20.1.1. Summary of the Invention [Problem to be solved by the invention]

[0016] There is still a need for improved therapies for the treatment of cancer.The combinations, methods, dosage regimens and uses disclosed herein are believed to have one or more advantages, such as greater efficacy than the treatment with any therapeutic agent alone; the possibility of reducing drug-drug interactions; the possibility of enabling improved dosing schedules; the possibility of reducing side effects; the possibility of overcoming resistance mechanisms. [Means for solving the problem]

[0017] The present disclosure relates to methods, combinations, dosage regimens, uses and pharmaceutical compositions for treating cancer in a subject in need thereof comprising a selective CDK2 inhibitor of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, and a selective CDK4 inhibitor such as a compound of formula (II) or a pharma- ceutically acceptable salt thereof.

[0018] In one aspect, the disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject: (a) an amount of a compound of formula (I):

[0019] [ka] or a pharma- ceutically acceptable salt or solvate thereof, R 1 is -L-(5- to 6-membered heteroaryl) or -L-(phenyl), wherein said 5- to 6-membered heteroaryl or phenyl is selected from 1 to 3 R 3 may be substituted by R 2 is C1-C6 alkyl or C3-C7 cycloalkyl, wherein said C3-C7 cycloalkyl is optionally substituted by C1-C4 alkyl; L is a bond or methylene; Each R 3 is independently C1-C4 alkyl, C1-C4 alkoxy, or SO2-C1-C4 alkyl, where each C1-C4 alkyl is optionally substituted by F, OH, or C1-C4 alkoxy; and (b) an amount of a selective cyclin-dependent kinase 4 (CDK4) inhibitor administering wherein the amounts of (a) and (b) together are effective to treat cancer. A method is provided.

[0020] In some embodiments of this aspect, the disclosure provides a method, further comprising administering to the subject (c) an amount of an additional anti-cancer agent, wherein the amounts of (a), (b), and (c) together are effective to treat the cancer.

[0021] In another aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising: (a) A compound of formula (I):

[0022] [ka] or a pharma- ceutically acceptable salt or solvate thereof, R 1is -L-(5- to 6-membered heteroaryl) or -L-(phenyl), wherein said 5- to 6-membered heteroaryl or phenyl is selected from 1 to 3 R 3 may be substituted by R 2 is C1-C6 alkyl or C3-C7 cycloalkyl, wherein said C3-C7 cycloalkyl is optionally substituted by C1-C4 alkyl; L is a bond or methylene; Each R 3 is independently C1-C4 alkyl, C1-C4 alkoxy, or SO2-C1-C4 alkyl, where each C1-C4 alkyl is optionally substituted by F, OH, or C1-C4 alkoxy; and (b) Selective cyclin-dependent kinase 4 (CDK4) inhibitors Including, wherein the combination of (a) and (b) is effective to treat cancer. A combination is provided.

[0023] In some embodiments of this aspect, the combination further comprises (c) an additional anti-cancer agent, where the combination of (a), (b) and (c) is effective to treat cancer.

[0024] In another aspect, the present disclosure provides a combination for use in treating cancer, comprising: (a) A compound of formula (I):

[0025] [ka] or a pharma- ceutically acceptable salt or solvate thereof, R 1 is -L-(5- to 6-membered heteroaryl) or -L-(phenyl), wherein said 5- to 6-membered heteroaryl or phenyl is selected from 1 to 3 R 3 may be substituted by R 2is C1-C6 alkyl or C3-C7 cycloalkyl, wherein said C3-C7 cycloalkyl is optionally substituted by C1-C4 alkyl; L is a bond or methylene; Each R 3 is independently C1-C4 alkyl, C1-C4 alkoxy, or SO2-C1-C4 alkyl, where each C1-C4 alkyl is optionally substituted by F, OH, or C1-C4 alkoxy; and (b) Selective cyclin-dependent kinase 4 (CDK4) inhibitors The present invention provides a combination comprising:

[0026] In some embodiments of this aspect, the combination for use further comprises (c) an additional anti-cancer agent.

[0027] In another aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising: (a) A compound of formula (I):

[0028] [ka] or a pharma- ceutically acceptable salt or solvate thereof, R 1 is -L-(5- to 6-membered heteroaryl) or -L-(phenyl), wherein said 5- to 6-membered heteroaryl or phenyl is selected from 1 to 3 R 3 may be substituted by R 2 is C1-C6 alkyl or C3-C7 cycloalkyl, wherein said C3-C7 cycloalkyl is optionally substituted by C1-C4 alkyl; L is a bond or methylene; Each R 3 is independently C1-C4 alkyl, C1-C4 alkoxy, or SO2-C1-C4 alkyl, where each C1-C4 alkyl is optionally substituted by F, OH, or C1-C4 alkoxy; and (b) Selective cyclin-dependent kinase 4 (CDK4) inhibitors Including, The use of the combination is effective in treating cancer. The use of combinations is provided.

[0029] In some embodiments of this aspect, the combination further comprises (c) an additional anti-cancer agent, where use of the combination of (a), (b) and (c) is effective to treat cancer.

[0030] In a preferred embodiment of each of the methods, combinations and uses herein, the compound of formula (I) has the structure:

[0031] [ka] and (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentylpropan-2-ylcarbamate (PF-07104091) or its monohydrate, which is a potent inhibitor of CDK2 having the formula:

[0032] In particularly preferred embodiments of each of the methods, combinations and uses described herein, the compound of formula (I) is PF-07104091 monohydrate.

[0033] In some embodiments of each of the methods, combinations and uses described herein, the combination of the compound of formula (I) and the selective CDK4 inhibitor is synergistic. In some embodiments of the methods, combinations and uses described herein, the combination of the compound of formula (I), the CDK4 inhibitor and the additional anticancer agent is synergistic.

[0034] In some embodiments of each of the methods, combinations, and uses described herein, the selective CDK4 inhibitor is a compound of formula (II):

[0035] [ka] or a pharma- ceutically acceptable salt thereof, R 4 is H, F or Cl, R 5 is H, C1-C5 alkyl, C1-C5 fluoroalkyl, or C3-C8 cycloalkyl, wherein each of said C1-C5 alkyl and C1-C5 fluoroalkyl is R 8 Each of said C3-C8 cycloalkyl may be substituted by R 9 may be substituted by R 6 is H, C1-C4 alkyl or C1-C4 fluoroalkyl, wherein each of said C1-C4 alkyl and C1-C4 fluoroalkyl is selected from the group consisting of R 8 may be substituted by R 7 is H, F or Cl, Each R 8 are independently OH, C1-C4 alkoxy or NR 10 R 11 and Each R 9 are independently F, C1-C4 alkyl, C1-C4 alkoxy or NR 10 R 11 and Each R 10 and R 11 are independently H or C1-C2 alkyl. It is.

[0036] In a preferred embodiment, the compound of formula (II) has the structure:

[0037] [ka] or a pharmaceutically acceptable salt thereof.

[0038] In a preferred embodiment of each of the methods, combinations and uses described herein, the compound of formula (I) is PF-07104091 or a pharma- ceutically acceptable solvate thereof and the compound of formula (II) is PF-07220060 or a pharma- ceutically acceptable salt thereof. In a particularly preferred embodiment of each of the methods, combinations and uses described herein, the compound of formula (I) is PF-07104091 monohydrate and the compound of formula (II) is PF-07220060.

[0039] In some embodiments of each of the methods, combinations and uses described herein, the present disclosure further comprises one or more additional anti-cancer agents.In a preferred embodiment, the cancer is breast cancer (including HR+ / HER2- breast cancer), and the additional anti-cancer agent is an endocrine therapeutic agent.In some such embodiments, the endocrine therapeutic agent is an aromatase inhibitor, a selective estrogen receptor degrader (SERD) or a selective estrogen receptor modulator (SERM).In a preferred embodiment, the endocrine therapeutic agent is letrozole or fulvestrant.

[0040] Each embodiment of the methods, combinations and uses described herein may be combined with one or more other embodiments, provided that such embodiments are not mutually inconsistent. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] The present disclosure may be more readily understood by reference to the following detailed description of preferred embodiments of the present disclosure and the examples contained herein. It should be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to be limiting. It should be further understood that, unless specifically defined herein, the terms used herein are given their customary meanings as known in the relevant technical field.

[0042] E1. A method of treating cancer in a subject in need thereof, comprising administering to the subject: (a) an amount of a compound of formula (I):

[0043] [ka] or a pharma- ceutically acceptable salt or solvate thereof, R 1 is -L-(5- to 6-membered heteroaryl) or -L-(phenyl), wherein said 5- to 6-membered heteroaryl or phenyl is selected from 1 to 3 R 3 may be substituted by R 2 is C1-C6 alkyl or C3-C7 cycloalkyl, wherein said C3-C7 cycloalkyl is optionally substituted by C1-C4 alkyl; L is a bond or methylene; Each R 3 is independently C1-C4 alkyl, C1-C4 alkoxy, or SO2-C1-C4 alkyl, where each C1-C4 alkyl is optionally substituted by F, OH, or C1-C4 alkoxy; and (b) an amount of a compound of formula (II):

[0044] [ka] or a pharma- ceutically acceptable salt thereof, R 4is H, F or Cl, R 5 is H, C1-C5 alkyl, C1-C5 fluoroalkyl, or C3-C8 cycloalkyl, wherein each of said C1-C5 alkyl and C1-C5 fluoroalkyl is R 8 Each of said C3-C8 cycloalkyl may be substituted by R 9 may be substituted by R 6 is H, C1-C4 alkyl or C1-C4 fluoroalkyl, wherein each of said C1-C4 alkyl and C1-C4 fluoroalkyl is selected from the group consisting of R 8 may be substituted by R 7 is H, F or Cl, Each R 8 are independently OH, C1-C4 alkoxy or NR 10 R 11 and Each R 9 are independently F, C1-C4 alkyl, C1-C4 alkoxy or NR 10 R 11 and Each R 10 and R 11 are independently H or C1-C2 alkyl. administering wherein the amounts of (a) and (b) together are effective to treat cancer. method.

[0045] E2. The method of embodiment E1, further comprising administering to the subject (c) an amount of an additional anti-cancer agent, wherein the amounts of (a), (b) and (c) together are effective to treat the cancer.

[0046] E3. The method of embodiment E1 or E2, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, bladder cancer, colon cancer, uterine cancer, prostate cancer, esophageal cancer, liver cancer, pancreatic cancer and gastric cancer.

[0047] E4. The method of embodiment E2 or E3, wherein the cancer is hormone receptor positive (HR+) breast cancer and the additional anticancer agent is an endocrine therapeutic agent selected from the group consisting of an aromatase inhibitor, a selective estrogen receptor modulator (SERM) and a selective estrogen receptor degrader (SERD).

[0048] E5. The method of embodiment E4, wherein the endocrine therapeutic agent is letrozole or fulvestrant.

[0049] E6. The method of any one of embodiments E1 to E3, wherein the cancer is lung cancer.

[0050] E7. The method of embodiment E6, wherein the lung cancer is small cell lung cancer (SCLC).

[0051] E8. The method of embodiment E7, wherein the SCLC is characterized by loss of retinoblast (RB) function.

[0052] E9. The method of embodiment E6, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0053] E10. The method of embodiment E9, wherein the NSCLC is lung squamous cell carcinoma (LUSC) or lung adenocarcinoma (LUAD).

[0054] E11. The method of embodiment E10, wherein the NSCLC is KRAS-driven lung adenocarcinoma (LUAD).

[0055] E12. The method of any one of embodiments E1 to E11, wherein the compound of formula (I) is (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentylpropan-2-ylcarbamate (PF-07104091) monohydrate.

[0056] E13. The method of embodiment E12, wherein the amount of PF-07104091 is from about 75 mg to about 500 mg BID.

[0057] E14. The method of embodiment E13, wherein the amount of PF-07104091 is about 75 mg BID, about 150 mg BID, or about 225 mg BID.

[0058] E15. The method of embodiment E12, wherein the amount of PF-07104091 is from about 100 mg to about 500 mg BID.

[0059] E16. The method of embodiment E15, wherein the amount of PF-07104091 is from about 150 mg to about 300 mg BID.

[0060] E17. The method of embodiment E15 or E16, wherein the amount of PF-07104091 is about 150 mg BID, about 225 mg BID or about 300 mg BID.

[0061] E18. The method of any one of embodiments E1 to E17, wherein the compound of formula (II) is 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (PF-07220060), or a pharma-ceutically acceptable salt thereof.

[0062] E19. The method of embodiment E18, wherein the amount of PF-07220060 is from about 100 mg to about 500 mg BID.

[0063] E20. The method of embodiment E19, wherein the amount of PF-07220060 is from about 300 mg to about 500 mg BID.

[0064] E21. The method of embodiment E20, wherein the amount of PF-07220060 is about 100 mg BID, about 200 mg BID or about 300 mg BID.

[0065] E22. The method of embodiment E19 or E20, wherein the amount of PF-07220060 is about 300 mg BID or about 400 mg BID.

[0066] E23. (a) A compound of formula (I):

[0067] [ka] or a pharma- ceutically acceptable salt or solvate thereof, R 1 is -L-(5- to 6-membered heteroaryl) or -L-(phenyl), wherein said 5- to 6-membered heteroaryl or phenyl is selected from 1 to 3 R 3 may be substituted by R 2 is C1-C6 alkyl or C3-C7 cycloalkyl, wherein said C3-C7 cycloalkyl is optionally substituted by C1-C4 alkyl; L is a bond or methylene; Each R 3 is independently C1-C4 alkyl, C1-C4 alkoxy, or SO2-C1-C4 alkyl, where each C1-C4 alkyl is optionally substituted by F, OH, or C1-C4 alkoxy; and (b) A compound of formula (II):

[0068] [ka] or a pharma- ceutically acceptable salt thereof, R 4 is H, F or Cl, R 5 is H, C1-C5 alkyl, C1-C5 fluoroalkyl, or C3-C8 cycloalkyl, wherein each of said C1-C5 alkyl and C1-C5 fluoroalkyl is R 8 Each of said C3-C8 cycloalkyl may be substituted by R 9 may be substituted by R6 is H, C1-C4 alkyl or C1-C4 fluoroalkyl, wherein each of said C1-C4 alkyl and C1-C4 fluoroalkyl is selected from the group consisting of R 8 may be substituted by R 7 is H, F or Cl, Each R 8 are independently OH, C1-C4 alkoxy or NR 10 R 11 and Each R 9 are independently F, C1-C4 alkyl, C1-C4 alkoxy or NR 10 R 11 and Each R 10 and R 11 are independently H or C1-C2 alkyl. Including, wherein the combination of (a) and (b) is effective to treat cancer. combination.

[0069] E24. The combination of embodiment E23, further comprising (c) an additional anti-cancer agent, wherein the combination of (a), (b) and (c) is effective to treat cancer.

[0070] E25. The combination of embodiment E23 or E24, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, bladder cancer, colon cancer, uterine cancer, prostate cancer, esophageal cancer, liver cancer, pancreatic cancer and gastric cancer.

[0071] E26. The combination of embodiment E24 or E25, wherein the cancer is hormone receptor positive (HR+) breast cancer and the additional anticancer agent is an endocrine therapeutic agent selected from the group consisting of an aromatase inhibitor, a selective estrogen receptor modulator (SERM) and a selective estrogen receptor degrader (SERD).

[0072] E27. The combination of embodiment E26, wherein the endocrine therapeutic agent is letrozole or fulvestrant.

[0073] E28. The combination of any one of embodiments E23 to E25, wherein the cancer is lung cancer.

[0074] E29. The combination of embodiment E28, wherein the lung cancer is small cell lung cancer (SCLC).

[0075] E30. The combination of embodiment E29, wherein the SCLC is characterized by loss of retinoblast (RB) function.

[0076] E31. The combination of embodiment E28, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0077] E32. The combination of embodiment E31, wherein the NSCLC is lung squamous cell carcinoma (LUSC) or lung adenocarcinoma (LUAD).

[0078] E33. The combination of embodiment E32, wherein the NSCLC is KRAS-driven lung adenocarcinoma (LUAD).

[0079] E34. The combination of any one of embodiments E23 to E33, wherein the compound of formula (I) is (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentylpropan-2-ylcarbamate (PF-07104091) monohydrate.

[0080] E35. The combination of embodiment E34, wherein the amount of PF-07104091 is from about 50 mg to about 250 mg BID.

[0081] E36. The combination of embodiment E35, wherein the amount of PF-07104091 is from about 75 mg to about 150 mg BID.

[0082] E37. The combination of embodiment E35 or E36, wherein the amount of PF-07104091 is about 75 mg BID, about 100 mg BID, about 125 mg BID or about 150 mg BID.

[0083] E38. The combination of embodiment E35, wherein the amount of PF-07104091 is about 75 mg BID, about 150 mg BID or about 225 mg BID.

[0084] E39. The combination of any one of embodiments E23 to E38, wherein the compound of formula (II) is 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (PF-07220060), or a pharma-ceutically acceptable salt thereof.

[0085] E40. The combination of embodiment E39, wherein the amount of PF-07220060 is from about 100 mg to about 500 mg BID.

[0086] E41. The combination of embodiment E40, wherein the amount of PF-07220060 is from about 300 mg to about 500 mg BID.

[0087] E42. The combination of embodiment E40 or E41, wherein the amount of PF-07220060 is about 300 mg BID or about 400 mg BID.

[0088] E43. The method of embodiment E40, wherein the amount of PF-07220060 is about 100 mg BID, about 200 mg BID or about 300 mg BID.

[0089] E44. A method of treating cancer in a subject in need thereof, comprising administering to the subject: (a) an amount of PF-07104091, and (b) an amount of PF-07220060, or a pharma- ceutically acceptable salt thereof; administering wherein the amounts of (a) and (b) together are effective to treat cancer. method.

[0090] E45. A method of treating cancer in a subject in need thereof, comprising administering to the subject: (a) an amount of PF-07104091; (b) an amount of PF-07220060, or a pharma- ceutically acceptable salt thereof, and (c) an amount of an additional anticancer agent. administering wherein the amounts of (a), (b), and (c) together are effective to treat cancer. method.

[0091] E46. The method of embodiment E44 or E45, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, bladder cancer, colon cancer, uterine cancer, prostate cancer, esophageal cancer, liver cancer, pancreatic cancer and gastric cancer.

[0092] E47. The method of any one of embodiments E44 to E46, wherein the cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer.

[0093] E48. The method of any one of embodiments E45 to E47, wherein the additional anticancer agent is an endocrine therapeutic agent selected from the group consisting of an aromatase inhibitor, a SERM, and a SERD.

[0094] E49. The method of embodiment E48, wherein the endocrine therapeutic agent is letrozole or fulvestrant.

[0095] E50. The method of any one of embodiments E44 to E46, wherein the cancer is lung cancer.

[0096] E51. The method of embodiment E50, wherein the lung cancer is small cell lung cancer (SCLC).

[0097] E52. The method of embodiment E51, wherein the SCLC is characterized by loss of retinoblast (RB) function.

[0098] E53. The method of embodiment E50, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0099] E54. The method of embodiment E53, wherein the NSCLC is lung squamous cell carcinoma (LUSC) or lung adenocarcinoma (LUAD).

[0100] E55. The method of embodiment E54, wherein the NSCLC is KRAS-driven lung adenocarcinoma (LUAD).

[0101] E56. The method of any one of embodiments E44 to E55, wherein the amount of PF-07104091 is from about 50 mg to about 250 mg BID.

[0102] E57. The method of embodiment E56, wherein the amount of PF-07104091 is from about 75 mg to about 150 mg BID.

[0103] E58. The method of embodiment E56 or E57, wherein the amount of PF-07104091 is about 75 mg BID, about 100 mg BID, about 125 mg BID or about 150 mg BID.

[0104] E59. The method of embodiment E56 or E57, wherein the amount of PF-07104091 is about 75 mg BID, about 150 mg BID or about 225 mg BID.

[0105] E60. The method of any one of embodiments E44 to E59, wherein the compound of formula (II) is 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (PF-07220060), or a pharma- ceutically acceptable salt thereof.

[0106] E61. The method of embodiment E60, wherein the amount of PF-07220060 is from about 100 mg to about 500 mg BID.

[0107] E62. The method of embodiment E61, wherein the amount of PF-07220060 is from about 300 mg to about 500 mg BID.

[0108] E63. The method of embodiment E61, wherein the amount of PF-07220060 is about 100 mg BID, about 200 mg BID or about 300 mg BID.

[0109] E64. The method of embodiment E61 or E62, wherein the amount of PF-07220060 is about 300 mg BID or about 400 mg BID.

[0110] E65. The method of any one of embodiments E1 to E22, wherein the cancer is a CDK4 / 6 inhibitor-resistant cancer.

[0111] E66. The method of embodiment E65, wherein the CDK4 / 6 inhibitor is palbociclib.

[0112] E67. The method of any one of embodiments E1 to E22, wherein the subject has previously been treated with a CDK4 / 6 inhibitor.

[0113] E68. The method of embodiment E67, wherein the CDK4 / 6 inhibitor is palbociclib.

[0114] Definition: As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated. For example, "a" substituent includes one or more substituents.

[0115] The disclosure described herein may suitably be practiced in the absence of any element not specifically disclosed herein. Thus, for example, in each instance herein, any of the terms "comprising," "consisting essentially of," and "consisting of" may be replaced with either of the other two terms.

[0116] The term "about" means an acceptable standard of error as considered by one of ordinary skill in the art. In some embodiments, the term "about" means having a value that falls within ±10% of the indicated value. For example, a dose of about 150 mg should be understood to mean that the dose can vary between 135 mg and 165 mg.

[0117] The terms "cancer," "cancerous," or "malignant" refer to or describe a physiological condition in a mammal that is typically characterized by unregulated cell growth. As used herein, cancer may refer to any malignant and / or invasive growth or tumor caused by abnormal cell growth, including solid tumors, named for the type of cells that form them, and cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include, but are not limited to, sarcomas and carcinomas. Examples of blood cancers include, but are not limited to, leukemia, lymphoma, and myeloma. The term cancer includes, but is not limited to, primary cancers that originate at a specific site in the body, metastatic cancers that have spread from where they began to other parts of the body, recurrence from a first primary cancer after remission, or second primary cancers, which are new primary cancers in a person with a history of previous cancers of a different type than the one that followed.

[0118] As used herein, "PF-07104091" may refer to PF-07104091 free base and / or PF-07104091 monohydrate. In a preferred embodiment, PF-07104091, as referred to herein, is PF-07104091 monohydrate.

[0119] As used herein, "dose-limiting toxicity" (DLT) refers to a dosage of, e.g., PF-07104091 or another agent described herein, where further escalation of the dosage is contraindicative.

[0120] As used herein, "maximum tolerated dose" (MTD) refers to the highest dosage of PF-07104091 or another agent described herein that does not cause unacceptable side effects or intolerable toxicity. The MTD is estimated based on the observed DLT rate and using the mTPI.

[0121] The term "patient" or "subject" refers to any single subject for whom therapy is desired, or who is participating in or used as a control in a clinical trial, epidemiological study, including humans and mammalian veterinary patients, e.g., domestic animals such as cows, horses, dogs and cats; non-human primates such as monkeys; laboratory animals such as rats, mice, guinea pigs; and captive wild animals such as lions, tigers, etc. In a preferred embodiment, the subject is a human.

[0122] In some embodiments, the subject is an adult human subject. In some embodiments, the adult subject is a woman or a man of any menopausal state. In some such embodiments, the subject is a postmenopausal woman or a man. In some such embodiments, the subject is a postmenopausal woman. In some such embodiments, the subject is a premenopausal or perimenopausal woman. In some such embodiments, the subject is a premenopausal or perimenopausal woman treated with a luteinizing hormone releasing hormone (LHRH) agonist. In some such embodiments, the subject is a man. In some such embodiments, the subject is a man treated with a LHRH agonist. In some embodiments, the subject is a human child between birth and 18 years of age. In some embodiments, the subject is a child between birth and 15 years of age with childhood cancer.

[0123] For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing (or destroying) the proliferation of neoplastic or cancerous cells; inhibiting metastasis or neoplastic cells; shrinking or reducing the size of a tumor; remission of cancer; reducing symptoms caused by cancer; increasing the quality of life of people suffering from cancer; reducing the dose of other drugs required to treat cancer; slowing the progression of cancer; curing cancer; overcoming one or more resistance mechanisms of cancer; and / or extending the survival of cancer patients. Positive therapeutic effects in cancer can be measured in a number of ways (see, for example, WA Weber, Assessing tumor response to therapy, J.Nucl.Med.50 Supplement 1:1S-10S (2009)). For example, with regard to tumor growth inhibition (T / C), according to the National Cancer Institute (NCI) criteria, a T / C of 42% or less is the minimum level of antitumor activity. A T / C of less than 10% was considered a high level of antitumor activity, where T / C(%)=median treated tumor volume / median control tumor volume×100.

[0124] The therapeutic effect of the methods, combinations and uses herein may be defined by referring to any of the following: partial response (PR), complete response (CR), progression-free survival (PFS), disease-free survival (DFS), duration of response (DoR), overall response rate (ORR) or overall survival (OS). In some embodiments, the response to the combinations, methods or uses disclosed herein is any of PR, CR, PFS, DFS, DoR, ORR or OS, which are assessed using RECIST v1.1 response criteria (Eisenhauer et al., New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1), Eur J of Cancer, 2009; 45(2): 228-47).

[0125] In some embodiments, the methods, combinations and uses herein relate to neoadjuvant therapy, adjuvant therapy, first line therapy, second line therapy, or third line or subsequent therapy. In each case, as further described herein, the cancer may be localized, advanced or metastatic, and the intervention may occur at any point along the disease continuum (i.e., at any stage of the cancer).

[0126] Treatment regimens for combinations, methods or uses that are effective for treating cancer in a subject may vary according to factors such as the disease state, age and weight of the subject, and the ability of the therapy to induce an anti-cancer response in the subject. Any embodiment of the aspects disclosed herein may not be effective in achieving a positive therapeutic effect in all subjects, but should be effective in a statistically significant number of subjects as determined by any statistical test known in the art, such as, for example, Student's t-test, chi-square test, Mann-Whitney U test, Kruskal-Wallis test (H test), Jonkheel-Tapstra test and Wilcon on test.

[0127] As used herein, "effective amount" or "therapeutically effective amount" for use and / or for treating a subject refers to an amount, in single or multiple doses, alone or in combination with one or more other agents, that provides a treatment, protocol, or therapeutic regimen, detectable response of any duration (transient, medium or long term), desired outcome in a subject, or objective or subjective benefit to a subject, to any measurable or detectable extent or for any duration (e.g., during remission or cure, over hours, days, months, years). Such an amount is typically effective to improve a disease, or one, more or all adverse effects / symptoms, consequences or complications of a disease, to a measurable extent, while reducing or inhibiting the progression or worsening of a disease, or providing a stable (i.e., non-worsening) state of a disease, is considered a satisfactory outcome. The term "therapeutically effective amount" also refers to an amount of an active agent that is effective to provide a desired therapeutic effect upon administration to a subject, for example, to stop the growth of or cause the shrinkage of a cancerous tumor.

[0128] Effective amount may vary according to factors such as disease state, age, sex and weight of the subject. In protective use, beneficial or desired outcome may include eliminating or reducing the risk of disease, reducing severity, or delaying onset. In therapeutic use, beneficial or desired outcome may include reducing the incidence of disease or improving one or more symptoms, reducing the dose of another drug used to treat the disease, enhancing the efficacy or safety of another drug used to treat the disease, delaying the time to disease progression, or prolonging survival.

[0129] As used herein, "treatment cycle" refers to a period of time that includes administration of one or more agents, with or without rest periods between treatment cycles. Treatment cycles can be continuous, i.e., without rest periods between treatment cycles. Alternatively, treatment cycles can be intermittent and include rest periods (i.e., dose interruption periods during which treatment is discontinued for one or more days or weeks) between treatment cycles. In such cases, administration of another agent during rest periods should not interfere with or be harmful to administration of the agent described herein.

[0130] For example, a 21-day or 28-day treatment cycle with 14 or 21 days of treatment, followed by a 7-day rest period (i.e., treatment interruption), respectively, is an example of an intermittent treatment cycle.A treatment cycle with 2 or 3 weeks of treatment and 1 week of treatment interruption is sometimes referred to as a 2 / 1 week or 3 / 1 week treatment cycle, respectively.Alternatively, an intermittent treatment cycle may include a 7-day cycle with 5 days of treatment and 2 days of treatment interruption.

[0131] As used herein, the term "ameliorate" refers to any reduction in the degree, severity, frequency and / or likelihood of a symptom or clinical sign characteristic of a particular disease. A "symptom" refers to any subjective evidence of a disease or of a subject's condition.

[0132] As used herein, "treating" or "treating" cancer and / or cancer-related disease means administering a single agent or combination therapy according to the present disclosure to a subject, patient or individual having or diagnosed with cancer, achieving at least one positive therapeutic effect, such as reducing the number of cancer cells, reducing tumor size, reducing the rate of cancer cell invasion into peripheral organs, or reducing the rate of tumor metastasis or growth, reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. The term "treating" also includes adjuvant and neoadjuvant treatment of a subject. For purposes of this disclosure, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: reducing (or destroying) the proliferation of neoplastic or cancerous cells; inhibiting metastasis or neoplastic cells; shrinking or reducing the size of a tumor; remission of cancer; reducing symptoms caused by cancer; increasing the quality of life of people suffering from cancer; reducing the dose of other drugs required to treat cancer; slowing the progression of cancer; curing cancer; overcoming one or more resistance mechanisms of cancer; and / or extending the survival of cancer patients. Positive therapeutic effects in cancer can be measured in a number of ways (see, e.g., WA Weber, J.Nucl.Med.50:1S-10S (2009)).

[0133] "Tumor" refers to a malignant or potentially malignant neoplasm or mass of tissue of any size, including primary and secondary neoplasms, when applied to a subject diagnosed with or suspected of having cancer. A solid tumor is an abnormal growth or mass of tissue that does not usually contain cysts or liquid areas. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) do not generally form solid tumors (National Cancer Institute, Cancer Glossary).

[0134] As used herein, the term "combination" or "combination therapy" refers to the administration of two or more therapeutic agents of the combination therapy, either as a compound or in the form of a pharmaceutical composition or medicament. The combination therapy may be administered sequentially, concurrently or simultaneously.

[0135] When administering a combination therapy of two or more agents, the agents may be administered in the same treatment cycle or using different cycles.In a preferred embodiment, PF-07104091 is administered continuously in a 28-day cycle.In a preferred embodiment, PF-07220060 is administered continuously in a 28-day cycle.Fulvestrant is typically administered intramuscularly on days 1, 15, 29 of the first treatment cycle and once a month thereafter.Letrozole is typically administered continuously in a 28-day treatment cycle.

[0136] Each therapeutic agent of the methods and combination therapies described herein may be administered in accordance with pharmaceutical practice either as a compound or in a pharmaceutical composition (also referred to herein as a medicament) comprising the therapeutic agent and one or more pharma- ceutically acceptable carriers, excipients or vehicles.

[0137] The term "sequential" or "sequentially" refers to the administration of each therapeutic agent of a combination therapy, either alone or as a pharmaceutical, one after the other, where each therapeutic agent can be administered in any order. Sequential administration can be particularly useful when the therapeutic agents in the combination therapy are in different dosage forms, for example, one agent is a tablet and another agent is a sterile liquid, and / or when the agents are administered according to different dosing schedules, for example, one agent is administered daily and the second agent is administered less frequently, such as weekly.

[0138] The term "concurrently" refers to the administration of each therapeutic agent in a combination therapy, either alone or in separate medicaments, where the second therapeutic agent is administered immediately after the first therapeutic agent, although the therapeutic agents can be administered in any order. In a preferred embodiment, the therapeutic agents are administered concurrently.

[0139] The term "concurrently" refers to the administration of each therapeutic agent of the combination therapy in the same pharmaceutical agent, for example, in a single dosage form as a fixed dose combination containing two or more drugs.

[0140] "Dosing regimen" refers to a period of administration of one or more drugs, compounds, or combinations, including one or more treatment cycles, where each treatment cycle may involve administration of one or more agents at different times, frequencies, or amounts, using the same or different routes of administration. Repeated administration or dosing regimens, or adjustments of administration or dosing regimens, may be performed as necessary to achieve a desired treatment effect.

[0141] "BID" or "bid" refers to administration of a drug, compound or composition twice daily.

[0142] "QD" or "qd" refers to the administration of a drug, compound or composition once daily.

[0143] "TID" or "tid" refers to the administration of a drug, compound or composition three times per day.

[0144] The term "additive" means that the result of the combination of two or more drugs, compounds or compositions is no greater than the sum of each drug, compound or composition individually.

[0145] The term "synergy" or "synergistic" means that the result of the combination of two or more drugs, compounds or compositions is greater than the sum of each drug, compound or composition individually. Combinations that provide a synergistic effect are sometimes referred to as synergistic combinations.

[0146] A "synergistic amount" is the amount of two or more drugs, compounds or compositions in combination that produces a synergistic effect. Synergistic effect can be calculated using a suitable method, such as, for example, the sigmoid Emax equation (Holford, NHG and Scheiner, LB, Clin. Pharmacokinet. 6:429-453 (1981)), the Loewe additivity equation (Loewe, S. and Muischnek, H., Arch. Exp. Pathol. Pharmacol. 114:313-326 (1926)) and the median effect equation (Chou, TC and Talalay, P., Adv. Enzyme Regul. 22:27-55 (1984)). Each of the above-mentioned equations can be fitted to experimental data to generate corresponding graphs to assist in assessing the effect of drug combinations. The corresponding graphs associated with the above-mentioned equations are the concentration-effect curve, the isobologram curve and the combination index curve, respectively. Ma&Motsinger-Reif, Current Method for Quantifying Drug Synergism, Proteom.Bioinform(2019)1(2):43~48;Tang et al., What is Synergy? The Saariselka Agreement Revisited, Front Pharmacol.(2015)Article 181, 6:1~5.

[0147] All references herein to CDK2 inhibitors of formula (I) or to CDK4 inhibitors of formula (II) include references (to the extent chemically feasible) to pharma- ceutically acceptable salts, solvates, hydrates and complexes thereof, and to pharma-ceutically acceptable solvates, hydrates and complexes of salts thereof, including amorphous and polymorphic forms, stereoisomers and isotopically labelled versions thereof.

[0148] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the parent compound. As used herein, the phrase "pharmaceutically acceptable salt" includes salts of acidic or basic groups that may be present in the compounds of the formulas disclosed herein, unless otherwise indicated. For example, compounds that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Of these, the acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds form non-toxic acid addition salts, i.e., salts that contain pharmacologically acceptable anions. Examples of suitable anions for the mono- and di-acid addition salts are acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, decanoate, edetate, edisleyate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hexylresorcinate, hydrabamine, hydroxynaphthoate, iodine ... The base salts include, but are not limited to, hydrate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucoate, napsylate, nitrate, octanoate, oleate, pamoate (embonate), pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate, sulfate, tannate, tartrate, theoclate, tosylate, triethionate and valerate. Alternatively, compounds that are acidic in nature can form base salts with various pharmacologically acceptable cations which form non-toxic base salts. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts, such as N-methylglucamine (meglumine), and lower alkanolammonium and other base salts of pharma- ceutically acceptable organic amines.Examples of suitable cations for such salts include alkali metal or alkaline earth metal salts and other cations, including aluminum, arginine, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, lithium, meglumine, potassium, procaine, sodium, triethylamine and zinc. Salts can be prepared by conventional techniques. Hemisalts of acids and bases can also be formed, such as hemisulfate and hemicalcium salts. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use, by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharma-ceutically acceptable salts are known to those skilled in the art.

[0149] Treatment methods, combinations and uses The present disclosure relates to a compound of formula (I):

[0150] [ka] or a pharma- ceutically acceptable salt or solvate thereof, R 1 is -L-(5- to 6-membered heteroaryl) or -L-(phenyl), wherein said 5- to 6-membered heteroaryl or phenyl is selected from 1 to 3 R 3 may be substituted by R 2 is C1-C6 alkyl or C3-C7 cycloalkyl, wherein said C3-C7 cycloalkyl is optionally substituted by C1-C4 alkyl; L is a bond or methylene; Each R 3 are independently C1-C4 alkyl, C1-C4 alkoxy, or SO2-C1-C4 alkyl, wherein each C1-C4 alkyl is optionally substituted by F, OH, or C1-C4 alkoxy. The present invention provides methods, combinations and uses comprising a CDK2 inhibitor which is

[0151] In each instance recited herein, references to "a compound of formula (I)" may be replaced by "a CDK2 inhibitor of formula (I)."

[0152] The present disclosure relates to a compound of formula (II):

[0153] [ka] or a pharma- ceutically acceptable salt or solvate thereof, R 4 is H, F or Cl, R 5 is H, C1-C5 alkyl, C1-C5 fluoroalkyl, or C3-C8 cycloalkyl, wherein each of said C1-C5 alkyl and C1-C5 fluoroalkyl is R 8 Each of said C3-C8 cycloalkyl may be substituted by R 9 may be substituted by R 6 is H, C1-C4 alkyl or C1-C4 fluoroalkyl, wherein each of said C1-C4 alkyl and C1-C4 fluoroalkyl is selected from the group consisting of R 8 may be substituted by R 7 is H, F or Cl, Each R 8 are independently OH, C1-C4 alkoxy or NR 10 R 11 and Each R 9 are independently F, C1-C4 alkyl, C1-C4 alkoxy or NR 10 R 11 and Each R 10 and R 11 are independently H or C1-C2 alkyl. The present invention further provides methods, combinations and uses comprising a selective CDK4 inhibitor,

[0154] In one aspect, the disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject: (a) an amount of a compound of formula (I):

[0155] [ka] or a pharma- ceutically acceptable salt or solvate thereof, R 1 is -L-(5- to 6-membered heteroaryl) or -L-(phenyl), wherein said 5- to 6-membered heteroaryl or phenyl is selected from 1 to 3 R 3 may be substituted by R 2 is C1-C6 alkyl or C3-C7 cycloalkyl, wherein said C3-C7 cycloalkyl is optionally substituted by C1-C4 alkyl; L is a bond or methylene; Each R 3 is independently C1-C4 alkyl, C1-C4 alkoxy, or SO2-C1-C4 alkyl, where each C1-C4 alkyl is optionally substituted by F, OH, or C1-C4 alkoxy; and (b) an amount of a compound of formula (II):

[0156] [ka] or a pharma- ceutically acceptable salt or solvate thereof, R 4 is H, F or Cl, R 5 is H, C1-C5 alkyl, C1-C5 fluoroalkyl, or C3-C8 cycloalkyl, wherein each of said C1-C5 alkyl and C1-C5 fluoroalkyl is R 8 Each of said C3-C8 cycloalkyl may be substituted by R 9 may be substituted by R 6is H, C1-C4 alkyl or C1-C4 fluoroalkyl, wherein each of said C1-C4 alkyl and C1-C4 fluoroalkyl is selected from the group consisting of R 8 may be substituted by R 7 is H, F or Cl, Each R 8 are independently OH, C1-C4 alkoxy or NR 10 R 11 and Each R 9 are independently F, C1-C4 alkyl, C1-C4 alkoxy or NR 10 R 11 and Each R 10 and R 11 are independently H or C1-C2 alkyl. administering wherein the amounts of (a) and (b) together are effective to treat cancer. A method is provided.

[0157] In some embodiments, the method further includes administering to the subject (c) an amount of an additional anti-cancer agent, where the amounts of (a), (b), and (c) together are effective to treat the cancer.

[0158] In another aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising: (a) A compound of formula (I):

[0159] [ka] or a pharma- ceutically acceptable salt or solvate thereof, R 1 is -L-(5- to 6-membered heteroaryl) or -L-(phenyl), wherein said 5- to 6-membered heteroaryl or phenyl is selected from 1 to 3 R 3 may be substituted by R 2is C1-C6 alkyl or C3-C7 cycloalkyl, wherein said C3-C7 cycloalkyl is optionally substituted by C1-C4 alkyl; L is a bond or methylene; Each R 3 is independently C1-C4 alkyl, C1-C4 alkoxy, or SO2-C1-C4 alkyl, where each C1-C4 alkyl is optionally substituted by F, OH, or C1-C4 alkoxy; and (b) A compound of formula (II):

[0160] [ka] or a pharma- ceutically acceptable salt or solvate thereof, R 4 is H, F or Cl, R 5 is H, C1-C5 alkyl, C1-C5 fluoroalkyl, or C3-C8 cycloalkyl, wherein each of said C1-C5 alkyl and C1-C5 fluoroalkyl is R 8 Each of said C3-C8 cycloalkyl may be substituted by R 9 may be substituted by R 6 is H, C1-C4 alkyl or C1-C4 fluoroalkyl, wherein each of said C1-C4 alkyl and C1-C4 fluoroalkyl is selected from the group consisting of R 8 may be substituted by R 7 is H, F or Cl, Each R 8 are independently OH, C1-C4 alkoxy or NR 10 R 11 and Each R 9 are independently F, C1-C4 alkyl, C1-C4 alkoxy or NR 10 R 11 and Each R 10 and R 11are independently H or C1-C2 alkyl. Including, wherein the combination of (a) and (b) is effective to treat cancer. A combination is provided.

[0161] In some embodiments, the combination further comprises (c) an additional anti-cancer agent, where the combination of (a), (b) and (c) is effective to treat cancer.

[0162] In another aspect, the present disclosure provides a combination for use in treating cancer, comprising: (a) A compound of formula (I):

[0163] [ka] or a pharma- ceutically acceptable salt or solvate thereof, R 1 is -L-(5- to 6-membered heteroaryl) or -L-(phenyl), wherein said 5- to 6-membered heteroaryl or phenyl is selected from 1 to 3 R 3 may be substituted by R 2 is C1-C6 alkyl or C3-C7 cycloalkyl, wherein said C3-C7 cycloalkyl is optionally substituted by C1-C4 alkyl; L is a bond or methylene; Each R 3 is independently C1-C4 alkyl, C1-C4 alkoxy, or SO2-C1-C4 alkyl, where each C1-C4 alkyl is optionally substituted by F, OH, or C1-C4 alkoxy; and (b) A compound of formula (II):

[0164] [ka] or a pharma- ceutically acceptable salt or solvate thereof, R 4is H, F or Cl, R 5 is H, C1-C5 alkyl, C1-C5 fluoroalkyl, or C3-C8 cycloalkyl, wherein each of said C1-C5 alkyl and C1-C5 fluoroalkyl is R 8 Each of said C3-C8 cycloalkyl may be substituted by R 9 may be substituted by R 6 is H, C1-C4 alkyl or C1-C4 fluoroalkyl, wherein each of said C1-C4 alkyl and C1-C4 fluoroalkyl is selected from the group consisting of R 8 may be substituted by R 7 is H, F or Cl, Each R 8 are independently OH, C1-C4 alkoxy or NR 10 R 11 and Each R 9 are independently F, C1-C4 alkyl, C1-C4 alkoxy or NR 10 R 11 and Each R 10 and R 11 are independently H or C1-C2 alkyl. The present invention provides a combination comprising:

[0165] In some embodiments, the combination for use further comprises (c) an additional anti-cancer agent.

[0166] In another aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising: (a) A compound of formula (I):

[0167] [ka] or a pharma- ceutically acceptable salt or solvate thereof, R 1 is -L-(5- to 6-membered heteroaryl) or -L-(phenyl), wherein said 5- to 6-membered heteroaryl or phenyl is selected from 1 to 3 R3 may be substituted by R 2 is C1-C6 alkyl or C3-C7 cycloalkyl, wherein said C3-C7 cycloalkyl is optionally substituted by C1-C4 alkyl; L is a bond or methylene; Each R 3 is independently C1-C4 alkyl, C1-C4 alkoxy, or SO2-C1-C4 alkyl, where each C1-C4 alkyl is optionally substituted by F, OH, or C1-C4 alkoxy; and (b) A compound of formula (II):

[0168] [ka] or a pharma- ceutically acceptable salt or solvate thereof, R 4 is H, F or Cl, R 5 is H, C1-C5 alkyl, C1-C5 fluoroalkyl, or C3-C8 cycloalkyl, wherein each of said C1-C5 alkyl and C1-C5 fluoroalkyl is R 8 Each of said C3-C8 cycloalkyl may be substituted by R 9 may be substituted by R 6 is H, C1-C4 alkyl or C1-C4 fluoroalkyl, wherein each of said C1-C4 alkyl and C1-C4 fluoroalkyl is selected from the group consisting of R 8 may be substituted by R 7 is H, F or Cl, Each R 8 are independently OH, C1-C4 alkoxy or NR 10 R 11 and Each R 9 are independently F, C1-C4 alkyl, C1-C4 alkoxy or NR 10 R 11 and Each R 10 and R 11 are independently H or C1-C2 alkyl. Including, wherein the use of the combination of (a) and (b) is effective in treating cancer. The use of combinations is provided.

[0169] In some embodiments of this aspect, the combination further comprises (c) an additional anti-cancer agent, where use of the combination of (a), (b) and (c) is effective to treat cancer.

[0170] In some embodiments of each of the methods, combinations and uses described herein, the compound of formula (I) has the structure:

[0171] [ka] The compound is (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentylpropan-2-ylcarbamate (PF-07104091), having the formula:

[0172] It is understood that the above structural formula of PF-07104091 encompasses all tautomeric forms that may coexist and be directly interconverted under appropriate conditions. For example, in some embodiments, PF-07104091 is

[0173] [ka] It has the structure:

[0174] In a preferred embodiment of each of the methods, combinations and uses described herein, the compound of formula (II) has the structure:

[0175] [ka] or a pharmaceutically acceptable salt thereof.

[0176] In another aspect, the disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject: (a) an amount of PF-07104091 monohydrate, and (b) an amount of PF-07220060, or a pharma- ceutically acceptable salt thereof; administering wherein the amounts of (a) and (b) together are effective to treat cancer. A method is provided.

[0177] In another aspect, the disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject: (a) an amount of PF-07104091 monohydrate; (b) an amount of PF-07220060, or a pharma- ceutically acceptable salt thereof, and (c) an amount of an additional anticancer agent. administering wherein the amounts of (a), (b), and (c) together are effective to treat cancer. A method is provided.

[0178] In another aspect, the disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject: (a) an amount of PF-07104091 monohydrate, and (b) an amount of a selective CDK4 inhibitor administering wherein the amounts of (a) and (b) together are effective to treat cancer. A method is provided.

[0179] In another aspect, the disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject: (a) an amount of PF-07104091 monohydrate; (b) an amount of a selective CDK4 inhibitor, and (c) an amount of an additional anticancer agent. administering wherein the amounts of (a), (b), and (c) together are effective to treat cancer. A method is provided.

[0180] In another aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising: (a) PF-07104091 monohydrate, and (b) PF-07220060 or a pharma- ceutically acceptable salt thereof. Including, wherein the combination of (a) and (b) is effective to treat cancer. A combination is provided.

[0181] In another aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising: (a) PF-07104091 monohydrate, (b) PF-07220060 or a pharma- ceutically acceptable salt thereof, and (c) Additional anticancer drugs Including, wherein the combination of (a), (b) and (c) is effective to treat cancer. A combination is provided.

[0182] In another aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising: (a) PF-07104091 monohydrate, and (b) Selective CDK4 inhibitors Including, wherein the combination of (a) and (b) is effective to treat cancer. A combination is provided.

[0183] In another aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising: (a) PF-07104091 monohydrate, (b) a selective CDK4 inhibitor, and (c) Additional anticancer drugs Including, wherein the combination of (a), (b) and (c) is effective to treat cancer. A combination is provided.

[0184] In another aspect, the present disclosure provides a combination for use in treating cancer, comprising: (a) PF-07104091 monohydrate, and (b) PF-07220060 or a pharma- ceutically acceptable salt thereof. The present invention provides a combination comprising:

[0185] In another aspect, the present disclosure provides a combination for use in treating cancer, comprising: (a) PF-07104091 monohydrate, (b) PF-07220060 or a pharma- ceutically acceptable salt thereof, and (c) Additional anticancer drugs The present invention provides a combination comprising:

[0186] In another aspect, the present disclosure provides a combination for use in treating cancer, comprising: (a) PF-07104091 monohydrate, and (b) Selective CDK4 inhibitors The present invention provides a combination comprising:

[0187] In another aspect, the present disclosure provides a combination for use in treating cancer, comprising: (a) PF-07104091 monohydrate, (b) a selective CDK4 inhibitor, and (c) Additional anticancer drugs The present invention provides a combination comprising:

[0188] In another aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising: (a) PF-07104091 monohydrate, and (b) PF-07220060 or a pharma- ceutically acceptable salt thereof. Including, wherein the use of the combination of (a) and (b) is effective in treating cancer. The use of combinations is provided.

[0189] In another aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising: (a) PF-07104091 monohydrate, (b) PF-07220060 or a pharma- ceutically acceptable salt thereof, and (c) Additional anticancer drugs Including, wherein the use of the combination of (a), (b) and (c) is effective in treating cancer. The use of combinations is provided.

[0190] In another aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising: (a) PF-07104091 monohydrate, and (b) Selective CDK4 inhibitors Including, wherein the use of a combination of (a) and (b) is effective in treating cancer. The use of combinations is provided.

[0191] In another aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising: (a) PF-07104091 monohydrate, (b) a selective CDK4 inhibitor, and (c) Additional anticancer drugs Including, wherein the use of the combination of (a), (b) and (c) is effective in treating cancer. The use of combinations is provided.

[0192] In some embodiments of each of the methods, combinations and uses described herein, the cancer is breast cancer, prostate cancer, lung cancer (including non-small cell lung cancer, NSCLC, and small cell lung cancer, SCLC), liver cancer (including hepatocellular carcinoma, HCC), kidney cancer (including renal cell carcinoma, RCC), bladder cancer (including urothelial carcinomas such as urothelial carcinoma of the upper urinary tract, UUTUC), ovarian cancer (including epithelial ovarian cancer, EOC), peritoneal cancer (including primary peritoneal carcinoma, PPC), Selected from the group consisting of fallopian tube cancer, cervical cancer, uterine cancer (including endometrial cancer), pancreatic cancer, gastric cancer, colorectal cancer, esophageal cancer, head and neck cancer (including squamous cell carcinoma of the head and neck (SCCHN), thyroid cancer and salivary gland cancer), testicular cancer, adrenal gland cancer, skin cancer (including basal cell carcinoma and melanoma), brain tumors (including astrocytoma, meningioma and glioblastoma), sarcoma (including osteosarcoma and liposarcoma) and lymphoma (including mantle cell lymphoma, MCL).

[0193] In some such embodiments, the cancer is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, bladder cancer, uterine cancer, colon cancer, prostate cancer, esophageal cancer, liver cancer, pancreatic cancer and gastric cancer.

[0194] In some embodiments of each of the methods, combinations and uses described herein, the cancer is characterized by amplification or overexpression of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2). In some such embodiments, the cancer is characterized by amplification or overexpression of cyclin E1 (CCNE1).

[0195] Examples of cyclin E overt cancers include, but are not limited to, ovarian cancer, breast cancer, liver cancer, gastric cancer, esophageal cancer, bladder cancer, uterine cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), colon cancer, prostate cancer or pancreatic cancer.

[0196] The retinoblastoma susceptibility gene (RB1) was the first molecularly defined tumor suppressor gene. The retinoblastoma gene product, RB, is frequently mutated or deleted in retinoblastoma and osteosarcoma, and is mutated or deleted at variable frequencies in other tumor types, including prostate cancer (including neuroendocrine prostate cancer), breast cancer (including triple-negative breast cancer, TNBC), lung cancer (including small cell lung cancer, SCLC, and non-small cell lung cancer, NSCLC), liver cancer, bladder cancer, ovarian cancer, uterine cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, glioblastoma, and lymphoma. In human cancers, the function of RB can be disrupted via neutralization by binding proteins (e.g., human papillomavirus-E7 protein in cervical cancer; Ishiji, T, 2000

[0021] , J Dermatol., 27:73-86) or deregulation of the pathway ultimately responsible for its phosphorylation.

[0197] "RB pathway" refers to the entire pathway of molecular signaling that includes the retinoblastoma protein (RB) and other proteins / protein families within the pathway, including but not limited to CDK, E2f, atypical protein kinase C, and Skp2. Inactivation of the RB pathway often occurs through perturbation of p16INK4a, cyclin D1, and CDK4.

[0198] The terms "RB+", "RB plus", "RB-proficient" or "RB positive" may be used to describe cells expressing detectable amounts of functional RB protein. RB-positive includes wild-type and non-mutated RB proteins. Wild-type RB (RB-WT) is generally understood to mean a form of RB protein that is typically present in the corresponding population and has the function currently assigned to the protein. RB positive may be a cell that contains a functional RB gene. A cell that is RB positive may also be a cell that is capable of encoding a detectable RB protein function.

[0199] The terms "RB-", "RB minus", "RB deficient" or "RB negative" describe several types of cells in which the function of RB is disrupted, including cells that produce undetectable amounts of functional RB protein. A cell that is RB negative can be a cell that does not contain a functional RB gene. A cell that is RB negative can also be a cell that can encode the RB protein, but in which the protein does not function properly.

[0200] In some embodiments of each of the methods and uses described herein, the cancer is characterized as retinoblastoma wild type (RB-WT). In some embodiments of each of the methods and uses described herein, the cancer is characterized as RB positive or RB proficiency. Such RB positive or RB proficiency cancer contains at least some functional retinoblastoma genes. In some embodiments, such RB-WT, RB positive or RB proficiency cancer is characterized as RB1-WT, RB1 positive or RB1 proficiency cancer.

[0201] In some embodiments of each of the methods, combinations and uses described herein, cancer is characterized as RB negative or RB deficient. Such RB negative or RB deficient cancer may be characterized by loss-of-function mutations that can code for missense mutations (i.e., coding for incorrect amino acids) or nonsense mutations (i.e., coding for stop codons). Alternatively, such RB negative cancer may be characterized by deletion of all or part of the retinoblastoma gene. In some embodiments, such RB negative or RB deficient cancer is characterized as RB1 negative or RB1 deficient.

[0202] In some embodiments of each of the methods, combinations, and uses described herein, the cancer is advanced or metastatic cancer.

[0203] In some embodiments of each of the methods, combinations and uses described herein, the cancer is refractory, i.e. the cancer does not respond at all to treatment with a therapeutic agent or class (including a standard of care agent or class), or responds initially but begins to grow again within a very short period of time.

[0204] In some embodiments of each of the methods, combinations, and uses described herein, the cancer is resistant to a therapeutic agent or class (including a standard of care agent or class). In some embodiments of each of the methods, combinations, and uses described herein, the cancer is characterized by innate or acquired resistance to a therapeutic agent or class (including a standard of care agent or class).

[0205] In some embodiments of each of the methods, combinations and uses described herein, the compound of formula (I) or its pharmaceutically acceptable salt or solvate and the compound of formula (II) or its pharmaceutically acceptable salt or solvate are administered sequentially, simultaneously or simultaneously.In some embodiments of each of the methods, combinations and uses described herein, PF-07104091 or its pharmaceutically acceptable salt or solvate and PF-07220060 or its pharmaceutically acceptable salt or solvate are administered sequentially, simultaneously or simultaneously.In some embodiments of each of the methods, combinations and uses described herein, PF-07104091 and the selective CDK4 inhibitor are administered sequentially, simultaneously or simultaneously.

[0206] In preferred embodiments of the methods, combinations and uses described herein, the cancer is breast cancer. In some embodiments of each of the breast cancer subtypes described herein, the breast cancer is advanced or metastatic breast cancer.

[0207] In some embodiments, the breast cancer is hormone receptor positive (HR+), i.e., the breast cancer is estrogen receptor positive (ER+) and / or progesterone receptor positive (PR+). In some embodiments, the breast cancer is hormone receptor negative (HR-), i.e., the breast cancer is estrogen receptor negative (ER-) and progesterone receptor negative (PR-).

[0208] In some embodiments, the cancer is HR+ breast cancer, the methods, combinations and uses described herein further comprise an additional anticancer agent, wherein the additional anticancer agent is an endocrine therapeutic agent.In some such embodiments, the endocrine therapeutic agent is an aromatase inhibitor, a SERD or a SERM.In a preferred embodiment, the endocrine therapeutic agent is letrozole or fulvestrant.

[0209] In some embodiments, the breast cancer is human epidermal growth factor receptor 2 negative (HER2-). In some embodiments, the breast cancer is human epidermal growth factor receptor 2 positive (HER2+).

[0210] In some embodiments, the breast cancer is associated with the BRCA1 or BRCA2 gene.

[0211] In a preferred embodiment, the breast cancer is HR+ / HER2- breast cancer. In some such embodiments, the HR+ / HER2- breast cancer is refractory to or has progressed during treatment with a CDK4 / 6 inhibitor. In some such embodiments, the HR+ / HER2- breast cancer is resistant to treatment with a CDK4 / 6 inhibitor, such as palbociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the HR+ / HER2- breast cancer is characterized by amplification or overexpression of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2). In some embodiments, the HR+ / HER2- breast cancer is characterized by amplification or overexpression of cyclin E1 (CCNE1). In some embodiments of each of the foregoing, the HR+ / HER2- breast cancer is advanced or metastatic HR+ / HER2- breast cancer.

[0212] In some embodiments, breast cancer is HR+ / HER2+ breast cancer. In other embodiments, breast cancer is HR- / HER2+ breast cancer. In some embodiments, breast cancer is HER2+, the methods, combinations and uses described herein further comprise an additional anti-cancer agent, wherein the additional anti-cancer agent is a HER2 targeting agent (e.g., trastuzumab emtansine, fam-trastuzumab deruxtecan, pertuzumab, lapatinib, neratinib or tucatinib), or an agent that targets the PI3K / AKT molecular pathway (e.g., ipatasertib).

[0213] In other embodiments, the breast cancer is triple-negative breast cancer (TNBC), i.e., the breast cancer is ER-, PR- and HER2-. In some embodiments, the TNBC is refractory or resistant to treatment with a CDK4 / 6 inhibitor, such as palbociclib or a pharma- ceutically acceptable salt thereof. In some embodiments, the TNBC is characterized by amplification or overexpression of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2). In some such embodiments, the TNBC is characterized by amplification or overexpression of cyclin E1 (CCNE1). In some embodiments, the TNBC is progressive or metastatic TNBC.

[0214] In some embodiments of each of the foregoing, the breast cancer is refractory to treatment with one or more standard of care agents. In some embodiments of each of the foregoing, the breast cancer is resistant to treatment with one or more standard of care agents.

[0215] In some such embodiments, the breast cancer is refractory or resistant to treatment with an endocrine therapeutic agent, such as an aromatase inhibitor, a SERD or a SERM. In some embodiments, the breast cancer is refractory or resistant to, or has progressed during, treatment with a CDK4 / 6 inhibitor. In other embodiments, the breast cancer is refractory or resistant to, or has progressed during, treatment with an anti-neoplastic chemotherapeutic agent, such as a platinum agent, a taxane, an anthracycline or an antimetabolite.

[0216] In some embodiments of each of the methods, combinations and uses described herein, the cancer is lung cancer. In some such embodiments, the lung cancer is advanced or metastatic lung cancer.

[0217] In some such embodiments, the lung cancer is small cell lung cancer (SCLC). In some such embodiments, the SCLC is characterized by loss of retinoblast (RB) function. In some such embodiments, the SCLC is progressive or metastatic SCLC. In some such embodiments, the SCLC is progressive or metastatic SCLC characterized by loss of retinoblast (RB) function.

[0218] In some embodiments of the methods and uses described herein, the cancer is SCLC. In some such embodiments, the SCLC is Rb negative or Rb deficient.

[0219] In some embodiments of the methods and uses described herein, the cancer is NSCLC. In some such embodiments, the NSCLC is characterized by the amplification or overexpression of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2). In some embodiments, the NSCLC is characterized by the amplification or overexpression of cyclin E1 (CCNE1). In some such embodiments, the NSCLC is advanced or metastatic NSCLC. In some such embodiments, the NSCLC is advanced or metastatic NSCLC characterized by the amplification or overexpression of cyclin E1 (CCNE1). In other embodiments, the NSCLC is lung squamous cell carcinoma (LUSC) or lung adenocarcinoma (LUAD). In a preferred embodiment, the lung cancer is LUAD. Single gene drive oncogene drivers of lung adenocarcinoma include but are not limited to EGFR, BRAF and KRAS. Approximately 25% of lung adenocarcinomas are KRAS driven, which can include KRAS G12C as well as non-G12C driven segments, including G12A, G12D, G12V, G13D and L19F driven tumors.

[0220] In some embodiments, the cancer is lung cancer, including SCLC or NSCLC, and the methods, combinations and uses described herein further comprise an additional anti-cancer agent.

[0221] In some embodiments of each of the methods, combinations and uses described herein, the cancer is ovarian cancer, peritoneal cancer or fallopian tube cancer (FTC). In some such embodiments, the ovarian cancer is epithelial ovarian cancer (EOC). In some such embodiments, the peritoneal cancer is primary peritoneal carcinomatosis (PPC). In some embodiments, the cancer is epithelial ovarian cancer (EOC), primary peritoneal carcinomatosis (PPC) or fallopian tube cancer (FTC). In some embodiments, the ovarian cancer is persistent, refractory or recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant ovarian cancer. In some such embodiments, the cancer is advanced or metastatic ovarian cancer. In some such embodiments, the cancer is platinum-resistant advanced or metastatic ovarian cancer. In some such embodiments, the cancer is advanced or metastatic EOC, PPC or FTC. In some such embodiments, the cancer is platinum-resistant advanced or metastatic EOC, PPC or FTC.

[0222] In some embodiments, each of the methods, combinations and uses described herein further comprises an additional anti-cancer drug.In some embodiments, the additional anti-cancer drug is a standard of care drug for the type of cancer.In some embodiments, each of the methods, combinations and uses described herein further comprises an additional anti-cancer drug, wherein the compound of formula (I) or its pharmaceutically acceptable salt or solvate, the compound of formula (II) or its pharmaceutically acceptable salt, and the additional anti-cancer drug are administered sequentially, simultaneously, or concurrently.

[0223] In some embodiments of each of the methods, combinations, and uses described herein, the cancer is breast cancer (including HR+ or HR+ / HER2- breast cancer), and the methods, combinations, and uses further comprise an additional anti-cancer agent. In some embodiments, the additional anti-cancer agent is an endocrine therapy. In some such embodiments, the endocrine therapy is an aromatase inhibitor, a SERD, or a SERM. In some embodiments, the endocrine therapy is an aromatase inhibitor. In some such embodiments, the aromatase inhibitor is selected from the group consisting of letrozole, anastrozole, and exemestane. In some preferred embodiments, the aromatase inhibitor is letrozole. In some embodiments, the endocrine therapy is a SERD. In some such embodiments, the SERD is selected from the group consisting of fulvestrant, elacestrant (RAD-1901, Radius Health), SAR439859 (Sanofi), RG6171 (Roche), AZD9833 (AstraZeneca), AZD9496 (AstraZeneca), lintodestrant (G1 Therapeutics), ZN-c5 (Zentalis), LSZ102 (Novartis), D-0502 (Inventisbio), LY3484356 (Lilly) and SHR9549 (Jiansu Hengrui Medicine). In some preferred embodiments, the SERD is fulvestrant. In some embodiments, the endocrine therapeutic agent is a SERM. In some such embodiments, the SERM is selected from the group consisting of tamoxifen, raloxifene, toremifene, lasofoxifene, bazedoxifene and afimoxifene. In some such embodiments, the SERM is tamoxifen or raloxifene.

[0224] In some embodiments of each of the methods, combinations, and uses described herein, the cancer is breast cancer (including HR+ or HR+ / HER2- breast cancer), and the methods, combinations, and uses further comprise an additional anti-cancer agent, where the compound of formula (I) is PF-07104091, the compound of formula (II) is PF-07220060 or a pharma- ceutically acceptable salt thereof, and the additional anti-cancer agent is an endocrine therapy, where the endocrine therapy is an aromatase inhibitor, a SERD, or a SERM. In some such embodiments, the endocrine therapy is letrozole or fulvestrant.

[0225] Pharmaceutical compositions, medicaments and kits The present disclosure relates to a compound of formula (I):

[0226] [ka] or a pharma- ceutically acceptable salt or solvate thereof, R 1 is -L-(5- to 6-membered heteroaryl) or -L-(phenyl), wherein said 5- to 6-membered heteroaryl or phenyl is selected from 1 to 3 R 3 may be substituted by R 2 is C1-C6 alkyl or C3-C7 cycloalkyl, wherein said C3-C7 cycloalkyl is optionally substituted by C1-C4 alkyl; L is a bond or methylene; Each R 3 are independently C1-C4 alkyl, C1-C4 alkoxy, or SO2-C1-C4 alkyl, wherein each C1-C4 alkyl is optionally substituted by F, OH, or C1-C4 alkoxy. Further provided are pharmaceutical compositions, medicaments and kits comprising:

[0227] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a selective CDK4 inhibitor or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or excipient. In some embodiments of this aspect, the pharmaceutical composition further comprises an additional anti-cancer agent (e.g., an endocrine therapeutic agent).

[0228] In another aspect, the present disclosure provides a first pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof and a pharma- ceutically acceptable carrier or excipient, and a second pharmaceutical composition comprising a compound of formula (II) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier or excipient, where the first and second pharmaceutical compositions are administered sequentially, simultaneously, or concomitantly. Some embodiments of this aspect further comprise a third pharmaceutical composition comprising an additional anti-cancer agent (e.g., an endocrine therapeutic agent) and a pharma- ceutically acceptable carrier or excipient, where the first, second, and third pharmaceutical compositions are administered sequentially, simultaneously, or concomitantly.

[0229] In another aspect, the disclosure provides a combination comprising a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, and a selective CDK4 inhibitor, or a pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for treating cancer in a subject.

[0230] In another aspect, the disclosure provides for the use of a combination comprising PF-07104091, or a pharma- ceutically acceptable solvate thereof, and PF-07220060, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject. In some embodiments of these aspects, the combination further comprises an additional anti-cancer agent (e.g., an endocrine therapeutic agent), for use in the manufacture of the medicament.

[0231] In another aspect, the disclosure provides a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating cancer, wherein the medicament is adapted for use in combination with a compound of formula (II) or a pharma- ceutically acceptable salt thereof. In another aspect, the disclosure provides a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating cancer, wherein the medicament is adapted for use in combination with a compound of formula (II) or a pharma- ceutically acceptable salt thereof and an additional anti-cancer agent, such as an endocrine therapeutic agent.

[0232] In a preferred embodiment of each of the pharmaceutical compositions, kits and medicaments described herein, the compound of formula (I) is PF-07104091 or a monohydrate thereof. In a preferred embodiment of each of the pharmaceutical compositions, kits and medicaments described herein, the compound of formula (II) is PF-07220060 or a pharma- ceutically acceptable salt thereof.

[0233] In particularly preferred embodiments of each of the pharmaceutical compositions, kits and medicaments described herein, the compound of formula (I) is PF-07104091 monohydrate and the compound of formula (II) is PF-07220060.

[0234] In another aspect, the disclosure provides a kit comprising a first container, a second container and a package insert, wherein the first container comprises at least one dose of a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof; the second container comprises at least one dose of a compound of formula (II) or a pharma- ceutically acceptable salt thereof; and the package insert comprises instructions for using the medicament to treat cancer in a subject. In some embodiments, the kit further comprises a third container, wherein the third container comprises at least one dose of an additional anti-cancer agent (e.g., an endocrine therapeutic agent); and the package insert comprises instructions for using the medicament to treat cancer in a subject.

[0235] In embodiments of the pharmaceutical compositions, medicaments and kits comprising an additional anti-cancer agent, the additional anti-cancer agent is an endocrine therapeutic agent, such as an aromatase inhibitor, a SERD or a SERM. In some such embodiments, the endocrine therapeutic agent is letrozole or fulvestrant.

[0236] The pharmaceutical compositions, medicaments and kits described herein can be useful for treating the cancers described above in relation to the methods, combinations and uses disclosed herein.In some embodiments, the pharmaceutical compositions, medicaments and kits can be useful for treating cancers selected from the group consisting of breast cancer (including HR+ / HER2-, HR+ / HER2+, HR- / HER2+ or TNBC), lung cancer (including SCLC or NSCLC), ovarian cancer (including EOC), peritoneal cancer (including PPC), fallopian tube cancer (including FTC), bladder cancer, colon cancer, uterine cancer, prostate cancer, esophageal cancer, liver cancer, pancreatic cancer and gastric cancer.

[0237] Dosage Forms and Regimen Each therapeutic agent included in the combinations, dosage regimens, methods and uses herein may be administered in accordance with pharmaceutical practice, either alone or as a medicament comprising the therapeutic agent and one or more pharma- ceutically acceptable carriers, excipients or vehicles (also referred to herein as a pharmaceutical composition).

[0238] As used herein, the term "combination" or "combination therapy" refers to the administration of two or more therapeutic agents of the combination therapy, either as a compound or in the form of a pharmaceutical composition. The combination therapy may be administered sequentially, concurrently or simultaneously.

[0239] In certain embodiments, when used in combination with PF-07220060, the effective daily amount of PF-07104091 (i.e., total daily dose) is from about 100 mg to about 500 mg per day, from about 100 mg to about 450 mg per day, from about 100 mg to about 400 mg per day, from about 100 mg to about 375 mg per day, from about 100 mg to about 350 mg per day, from about 100 mg to about 325 mg per day, or from about 100 mg to about 500 mg per day. g, from about 100 mg to about 300 mg per day, from about 100 mg to about 275 mg per day, from about 100 mg to about 250 mg per day, from about 100 mg to about 225 mg per day, from about 100 mg to about 200 mg per day, from about 100 mg to about 175 mg per day, from about 100 mg to about 150 mg per day, from about 150 mg to about 500 mg per day, from about 150 mg to about 450 mg per day , from about 150 mg to about 400 mg per day, from about 150 mg to about 375 mg per day, from about 150 mg to about 350 mg per day, from about 150 mg to about 325 mg per day, from about 150 mg to about 300 mg per day, from about 150 mg to about 275 mg per day, from about 150 mg to about 250 mg per day, from about 150 mg to about 225 mg per day, from about 150 mg to about 200 mg per day, from about 200 mg to about 500 mg per day, from about 200 mg to about 450 mg per day, from about 200 mg to about 400 mg per day, from about 200 mg to about 375 mg per day, from about 200 mg to about 350 mg per day, from about 200 mg to about 325 mg per day, from about 200 mg to about 300 mg per day, from about 200 mg to about 275 mg per day, or from about 200 mg to about 250 mg per day.

[0240] In certain embodiments, an effective amount of PF-07104091 when administered QD in combination with PF-07220060 is from about 100 mg to about 500 mg QD, from about 100 mg to about 450 mg QD, from about 100 mg to about 400 mg QD, from about 100 mg to about 375 mg QD, from about 100 mg to about 350 mg QD, from about 100 mg to about 325 mg QD, from about 100 mg to about 300 mg QD, from about 100 mg to about 275 mg QD, from about 100 mg to about 250 mg QD, from about 100 mg to about 225 mg QD, from about 100 mg to about 200 mg QD, from about 100 mg to about 175 mg QD, from about 100 mg to about 150 mg QD, from about 150 mg to about 500 mg QD, QD, about 150mg to about 450mg QD, about 150mg to about 400mg QD, about 150mg to about 375mg QD, about 150mg to about 350mg QD, about 150mg to about 325mg QD, about 150mg to about 300mg QD, about 150mg to about 275mg QD, about 150mg to about 250mg QD, about 150mg to about 225mg QD, about 150mg to about 200mg QD, about 200mg to about 500mg QD, about 200mg to about 450mg QD, about 200mg to about 400mg QD, about 200mg to about 375mg QD, about 200mg to about 350mg QD, about 200mg to about 325mg QD, from about 200 mg to about 300 mg QD, from about 200 mg to about 275 mg QD, from about 200 mg to about 250 mg QD.

[0241] In a preferred embodiment, an effective amount of PF-07104091 when administered BID in combination with PF-07220060 is from about 50 mg to about 250 mg BID, from about 50 mg to about 225 mg BID, from about 50 mg to about 200 mg BID, from about 50 mg to about 175 mg BID, from about 50 mg to about 150 mg BID, from about 50 mg to about 125 mg BID, from about 50 mg to about 100 mg BID, from about 75 mg to about 250 mg BID, from about 75 mg to about 225 mg BID, from about 75 mg to about 200 mg BID, from about 75 mg to about 175 mg BID, from about 75 mg to about 150 mg BID, from about 75 mg to about 125 mg BID, from about 75 mg to about 100 mg BID, from about 100 mg to about 250 mg BID, about 100 mg to about 225 mg BID, about 100 mg to about 200 mg BID, about 100 mg to about 175 mg BID, about 100 mg to about 150 mg BID, or about 100 mg to about 125 mg BID.

[0242] In some embodiments, when used in combination with PF-07220060, PF-07104091 is administered at a dose of about 100 mg per day, about 150 mg per day, about 200 mg per day, about 250 mg per day, about 300 mg per day, about 350 mg per day, or about 400 mg per day.

[0243] In some embodiments, when used in combination with PF-07220060, PF-07104091 is administered at a QD dose of about 100 mg QD, about 150 mg QD, about 200 mg QD, about 250 mg QD, about 300 mg QD, about 350 mg QD, or about 400 mg QD.

[0244] In some embodiments, when used in combination with PF-07220060, PF-07104091 is administered at a BID dose of about 50 mg BID, about 75 mg BID, about 100 mg BID, about 125 mg BID, about 150 mg BID, about 175 mg BID, or about 200 mg BID.

[0245] In a preferred embodiment, PF-07104091 is administered on a twice-daily (BID) dosing schedule. In a preferred embodiment, the effective amount of PF-07104091 when used in combination with PF-07220060 is about 75 mg BID, about 100 mg BID, about 125 mg BID, or about 150 mg BID.

[0246] In certain embodiments, when used in combination with PF-07104091, the therapeutically effective amount of PF-07220060 is from about 200 mg to about 1000 mg per day (i.e., total daily dose), e.g., from about 200 mg to about 500 mg per day, from about 200 mg to about 450 mg, from about 200 mg to about 400 mg, from about 200 mg to about 350 mg, from about 200 mg to about 300 mg, from about 400 mg to about 950 mg, mg, about 400 mg to about 900 mg, about 400 mg to about 850 mg, about 400 mg to about 800 mg, about 500 mg to about 950 mg, about 500 mg to about 900 mg, about 500 mg to about 850 mg, about 500 mg to about 800 mg, about 600 mg to about 950 mg, about 600 mg to about 900 mg, about 600 mg to about 850 mg, or about 600 mg to about 800 mg.

[0247] In certain embodiments, when used in combination with PF-07104091, PF-07220060 is administered at a dose of about 200 mg to about 1000 mg once daily (QD), e.g., about 200 mg to about 500 mg QD, about 200 mg to about 450 mg QD, about 200 mg to about 400 mg QD, about 200 mg to about 350 mg QD, about 200 mg to about 300 mg QD, about 400 mg to about 950 mg QD, about 400 mg to about 900 mg QD, about 400 mg to about 850 mg QD, about 400 mg to about 800 mg QD, about 500 mg to about 950 mg QD, about 500 mg to about 900 mg QD, about 500 mg to about 850 mg QD, about 500 mg to about 800 mg QD, QD, about 600 mg to about 950 mg QD, about 600 mg to about 900 mg QD, about 600 mg to about 850 mg QD, or about 600 mg to about 800 mg QD.

[0248] In certain embodiments, when used in combination with PF-07104091, a therapeutically effective amount of PF-07220060 is from about 100 mg to about 500 mg twice daily (BID), e.g., from about 200 mg to about 500 mg BID, from about 250 mg to about 500 mg BID, from about 300 mg to about 500 mg BID, from about 350 mg to about 500 mg BID, from about 400 mg to about 500 mg BID, from about 200 mg to about 450 mg BID, from about 250 mg to about 450 mg BID, from about 300 mg to about 450 mg BID, from about 350 mg to about 450 mg BID, from about 400 mg to about 450 mg BID, from about 200 mg to about 400 mg BID, from about 250 mg to about 400 mg BID, from about 300 mg to about 400 mg BID, or from about 350 mg to about 400 mg BID.

[0249] In some embodiments, a subject is administered PF-07220060, when used in combination with PF-07104091, at a dose of about 200 mg to about 1000 mg per day, e.g., a daily dose of about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg.

[0250] In some embodiments, PF-07220060 is administered at a dose of about 200 mg QD, about 300 mg QD, about 400 mg QD, about 500 mg QD, about 600 mg QD, about 700 mg QD, about 800 mg QD, about 900 mg QD, or about 1000 mg QD.

[0251] In preferred embodiments, PF-07220060, when used in combination with PF-07104091, is administered at a dose of about 100 mg BID, about 200 mg BID, about 300 mg BID, about 400 mg BID, or about 500 mg BID.

[0252] In some embodiments, the subject is administered PF-07104091 and PF-07220060 in any of the effective amounts disclosed herein.

[0253] In some embodiments, the subject is administered about 75 mg BID of PF-07104091 and about 100 mg BID of PF-07220060. In some embodiments, the subject is administered about 150 mg BID of PF-07104091 and about 100 mg BID of PF-07220060. In some embodiments, the subject is administered about 225 mg BID of PF-07104091 and about 100 mg BID of PF-07220060. In some embodiments, the subject is administered about 75 mg BID of PF-07104091 and 200 mg BID of PF-07220060. In some embodiments, the subject is administered about 150 mg BID of PF-07104091 and about 200 mg BID of PF-07220060. In some embodiments, the subject is administered about 225 mg BID of PF-07104091 and about PF-07220060. In some embodiments, the subject is administered about 75 mg BID of PF-07104091 and about 300 mg BID of PF-07220060. In some embodiments, the subject is administered about 150 mg BID of PF-07104091 and about 300 mg BID of PF-07220060. In some embodiments, the subject is administered about 225 mg BID of PF-07104091 and about 300 mg BID of PF-07220060.

[0254] The amount of PF-07104091 and PF-07220060 administered may be increased or decreased based on the weight, age, health, sex, or medical condition of the subject. One of ordinary skill in the art would be able to determine the appropriate dose for a subject based on this disclosure.

[0255] When administering a combination therapy including PF-07104091 and PF-07220060, the agents may be administered in the same treatment cycle or using different treatment cycles.

[0256] PF-07104091 and PF-07220060 may be administered in treatment cycles with or without rest periods between treatment cycles. Treatment cycles may have a duration of about 7 days, about 14 days, about 21 days, about 28 days, about 35 days, etc., or any number of days in between. The rest period can be one or several days (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, etc.), a week, several weeks (e.g., 2 weeks, 3 weeks, etc.), or any number of days in between (e.g., 1 week and 3 days).

[0257] In some embodiments, PF-07104091 is administered continuously with no rest periods between treatment cycles (i.e., continuous treatment until completion). In some embodiments, PF-07104091 is administered for treatment cycles (e.g., about 28 days) with or without rest periods. In some embodiments, PF-07104091 is administered for about 28 days with about a week of rest. PF-07104091 may be administered for at least about 7 days, about 14 days, about 21 days, about 28 days, about 2 months, about 3 months, about 12 months, about 24 months or more. In a preferred embodiment, PF-07104091 is administered continuously with 28-day treatment cycles with no rest periods.

[0258] In some embodiments, PF-07220060 is administered continuously with no rest periods between treatment cycles (i.e., continuous treatment until completion). In some embodiments, PF-07220060 is administered for treatment cycles (e.g., about 28 days) with or without rest periods. In some embodiments, PF-07220060 is administered for about 28 days with about a one week rest period. 07220060 may be administered for at least about 7 days, about 14 days, about 21 days, about 28 days, about 2 months, about 3 months, about 12 months, about 24 months or more. In a preferred embodiment, 07220060 is administered continuously with 28 day treatment cycles with no rest periods.

[0259] The pharmaceutical composition may be administered with or without food.

[0260] Pharmaceutical compositions may be administered by one or more routes as deemed appropriate by those skilled in the art and depending on the dosage form. Pharmaceutical compositions may be administered with or without food. Drug formulations are discussed in Remington's Pharmaceutical Sciences, 18th Edition (1995) Mack Publishing Co., Easton, Pa. Other examples of drug formulations can be found in Liberman, HA and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, Vol. 3, 2nd Edition, New York, NY. When a compound is administered orally, it may be formulated as a pill, capsule, tablet, etc., with pharmaceutically acceptable carriers, glidants or excipients.

[0261] The pharmaceutical composition may be in one or more dosage forms (eg, a capsule, tablet, powder, or liquid).

[0262] In some embodiments of each of the methods, combinations and uses herein, the combination therapy is administered to a subject who has not previously received treatment, i.e., is treatment naive.

[0263] In some embodiments of each of the methods, combinations and uses herein, the combination therapy is administered to subjects who have failed to achieve a durable response after previous therapy with a biological or chemotherapeutic agent, i.e., are treatment-experienced.

[0264] In some embodiments of each of the methods, combinations and uses herein, the combination therapy may be administered to a subject who has previously been treated with chemotherapy, radiation therapy and / or surgical resection.

[0265] In certain embodiments of each of the methods, combinations and uses herein, the subject has previously been treated with a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is palbociclib.

[0266] In some embodiments of each of the methods, combinations and uses herein, the invention relates to neoadjuvant therapy, adjuvant therapy, first line therapy, second line therapy, or third or subsequent line therapy for treating cancer, in each case as further described herein. In each of the foregoing embodiments, the cancer may be localized, advanced or metastatic, and the intervention may occur at any point along the disease continuum (i.e., at any stage of the cancer).

[0267] Dosage regimen can be adjusted to provide the optimum desired response. For example, the therapeutic agents of the combination therapy disclosed herein can be administered as a single bolus, as several divided doses administered over time, or the dose can be proportionally reduced or increased as dictated by the exigencies of the therapeutic situation. It can be particularly advantageous to formulate the therapeutic agents in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suitable as unitary dosages for the mammalian subject to be treated, each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect together with the required pharmaceutical carrier. The specifications of dosage unit form can be dictated by and directly depend on (a) the unique characteristics of the chemotherapeutic agent and the specific therapeutic or protective effect to be achieved, and (b) the limitations inherent in the technical field of compounding such active compounds for the treatment of susceptibility in an individual.

[0268] In some embodiments, the endocrine therapeutic agent is letrozole, which may be administered orally daily at a dose of 2.5 mg. In some embodiments, the endocrine therapeutic agent is fulvestrant, which may be administered intramuscularly in one or two injections at a dose of 250 mg or 500 mg, respectively, on days 1, 15, and 29 of the first month and then monthly thereafter.

[0269] In some embodiments, the compound of formula (I) and the compound of formula (II) are administered on an intermittent dosing schedule. In other embodiments, the compound of formula (I) and the compound of formula (II) are administered on a continuous dosing schedule.

[0270] In yet other embodiments, one of the compound of formula (I) and the compound of formula (II) is administered on an intermittent dosing schedule (e.g., a 2 / 1 week or 3 / 1 week schedule) and the other is administered on a continuous dosing schedule. In some such embodiments, the compound of formula (I) is administered on an intermittent dosing schedule and the compound of formula (II) is administered on a continuous dosing schedule. In other such embodiments, the compound of formula (I) is administered on a continuous dosing schedule and the compound of formula (II) is administered on an intermittent dosing schedule.

[0271] In some embodiments disclosed herein, the compound of formula (I) and the compound of formula (II) are administered in amounts that are together effective to treat cancer.

[0272] In some embodiments disclosed herein, the compound of formula (I) and the compound of formula (II) are administered in amounts that are synergistic together.

[0273] In some embodiments disclosed herein, the compound of formula (I) and the compound of formula (II) are dosed in amounts that are additive together.

[0274] In preferred embodiments of each of the foregoing, the compound of formula (I) is PF-07104091 or a monohydrate thereof and the compound of formula (II) is PF-07220060 or a pharma- ceutically acceptable salt thereof. In particularly preferred embodiments of each of the foregoing, the compound of formula (I) is PF-07104091 monohydrate and the compound of formula (II) is PF-07220060.

[0275] Pharmaceutical Compositions and Routes of Administration "Pharmaceutical composition" refers to a mixture of, as an active ingredient, one or more of the therapeutic agents described herein, or pharma- ceutically acceptable salts, solvates, hydrates, or prodrugs thereof, and at least one pharma- ceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises two or more pharma- ceutically acceptable carriers and / or excipients.

[0276] As used herein, a "pharmaceutically acceptable carrier" refers to a carrier or excipient that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of an active compound or therapeutic agent.

[0277] Pharmaceutically acceptable carriers can include any conventional pharmaceutical carrier or excipient. The choice of carrier and / or excipient will depend to a large extent on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0278] Suitable pharmaceutical carriers include inert excipients or fillers, water, and various organic solvents (such as hydrates and solvates). Pharmaceutical compositions may contain additional ingredients such as flavorings, binders, additives, etc., if desired. Thus, for oral administration, tablets containing various additives such as citric acid may be used together with various disintegrants such as starch, alginic acid, and certain complex silicates, and binders such as sucrose, gelatin, and acacia. Examples of additives include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often useful for tableting purposes. Similar types of solid compositions may also be used in soft and hard-filled gelatin capsules. Thus, non-limiting examples of materials include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof, together with various sweetening or flavoring agents, coloring agents, and optionally emulsifying or suspending agents.

[0279] The pharmaceutical compositions may be in a form suitable for example for oral administration as tablets, capsules, pills, powders, solutions or suspensions; for parenteral injection as sterile solutions, suspensions or emulsions; for topical administration as ointments or creams; or for rectal administration as suppositories.

[0280] Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered, if desired.

[0281] The pharmaceutical compositions may be in unit dosage forms suitable for single administration of precise amounts.

[0282] Pharmaceutical compositions suitable for delivery of the therapeutic agents of the combination therapies disclosed herein and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety.

[0283] The therapeutic agents of the combination therapies disclosed herein may be administered orally, which may involve swallowing so that the therapeutic agent enters the digestive tract, or buccal or sublingual administration may be used, where the therapeutic agent enters the bloodstream directly from the mouth.

[0284] Formulations suitable for oral administration include solid formulations, such as tablets, particles, capsules containing liquids or powders, lozenges (containing liquid fills), chewable tablets, multi- and nanoparticles, gels, solid liquids, liposomes, films (including mucoadhesives), ovules, sprays and liquid formulations.

[0285] Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations can be used as fillers in soft or hard capsules, and typically contain carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils, and one or more emulsifiers and / or suspending agents.Liquid formulations can also be prepared by reconstitution of solids, for example, from sachets.

[0286] The therapeutic agents of the combination therapy disclosed herein may be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11(6), 981-986, by Liang and Chen (2001), the disclosure of which is incorporated herein by reference in its entirety.

[0287] In tablet dosage forms, the therapeutic agent may comprise 1 wt% to 80 wt% of the dosage form, more typically 5 wt% to 60 wt% of the dosage form. In addition to the active agent, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant may comprise 1 wt% to 25 wt%, preferably 5 wt% to 20 wt% of the dosage form.

[0288] Binders are generally used to impart adhesive qualities to tablet formulations.Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.Tablets may also contain excipients such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and calcium hydrogen phosphate dihydrate.

[0289] Tablets may also contain surface active agents such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. If present, surface active agents typically amount to from 0.2 wt% to 5 wt% of the tablet, and glidants typically amount to from 0.2 wt% to 1 wt% of the tablet.

[0290] Tablets generally also contain a lubricant such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants are generally present in an amount from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.

[0291] Other conventional ingredients include antioxidants, colorants, flavorants, preservatives and taste-masking agents.

[0292] An exemplary tablet may contain up to about 80 wt% active agent, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% excipient, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.

[0293] Tablet blends may be directly or roller compressed to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry- or melt-granulated, melt congealed or extruded prior to tabletting. The final formulation may comprise one or more layers and may be coated or uncoated or encapsulated.

[0294] Tablet formulation is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1," by H. Lieberman and L. Lachman, Marcel Dekker, NY, NY, 1980 (ISBN 0-8247-6918-X), the disclosure of which is incorporated herein by reference in its entirety.

[0295] Solid formulations for oral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

[0296] Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies, such as high energy dispersions and osmotic and coated particles, can be found in Verma et al., Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO2000 / 035298. The disclosures of these references are incorporated herein in their entirety by reference.

[0297] The kit described herein can be particularly suitable for administering different dosage forms, for example oral and parenteral, administering different compositions at different dosage intervals, or titrating different compositions against each other.To aid in compliance, the kit typically includes administration instructions and can be equipped with memory aids.The kit can further include other materials that can be useful for administering medicaments, such as excipients, filters, IV bags and lines, needles and syringes, etc.

[0298] Additional anticancer drugs The methods, combinations and uses disclosed herein may additionally comprise one or more additional anti-cancer agents, such as anti-angiogenic agents, signal transduction inhibitors or anti-neoplastic agents described below, wherein the amount is effective to treat cancer together.In some embodiments, the methods, combinations and uses disclosed herein, the additional anti-cancer agent may comprise a palliative care agent.The additional anti-cancer agent may comprise a small molecule therapeutic agent and its pharmaceutically acceptable salt or solvate, a therapeutic antibody, an antibody drug conjugate (ADC), a heterobifunctional proteolytic agent (e.g., proteolytic-inducing chimeric molecule or PROTAC), or an antisense molecule.

[0299] In some embodiments, the methods, combinations and uses disclosed herein further comprise one or more additional anti-cancer agents selected from the following:

[0300] Anti-angiogenic agents include, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKCβ inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrin (alpha-v / beta-3), MMP-2 (matrix-metalloproteinase 2) inhibitors and MMP-9 (matrix-metalloproteinase 9) inhibitors.

[0301] Signal transduction inhibitors include, for example, kinase inhibitors (e.g., inhibitors of tyrosine kinase, serine / threonine kinase, or cyclin-dependent kinase), proteasome inhibitors, PI3K / AKT / mTOR pathway inhibitors, phosphoinositide 3 kinase (PI3K) inhibitors, isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) inhibitors, B-cell lymphoma 2 (BCL2) inhibitors, neurotrophin receptor kinase (NTRK) inhibitors, rearranged upon transfection (RET) inhibitors, Notch inhibitors, PARP inhibitors, Hedgehog pathway inhibitors, and selective inhibitors of nuclear export (SINE).

[0302] Examples of signal transduction inhibitors include acalabrutinib, afatinib, alectinib, alpelisib, axitinib, binimetinib, bortezomib, bosutinib, brigatinib, cabozantinib, carfilzomib, ceritinib, cobimetinib, copanlisib, crizotinib, dabrafenib, dacomitinib, dasatinib, duvelisib, enasidenib, encorafenib, entrectinib, erlotinib, gefitinib, gilteritinib, glasdegib, ibrutinib, idelalisib, imatinib, ipa including, but not limited to, tasertib, ivosidenib, ixazomib, lapatinib, larotrectinib, lenvatinib, lorlatinib, midostaurin, neratinib, nilotinib, niraparib, olaparib, osimertinib, pazopanib, ponatinib, regorafenib, rucaparib, ruxolitinib, sonidegib, sorafenib, sunitinib, talazoparib, trametinib, vandetanib, vemurafenib, venetoclax and vismodegib, or pharmaceutically acceptable salts and solvates thereof.

[0303] Anti-neoplastic agents include, for example, alkylating agents, platinum coordination complexes, cytotoxic antibiotics, antimetabolites, biological response modifiers, histone deacetylase (HDAC) inhibitors, hormonal agents, monoclonal antibodies, growth factor inhibitors, taxanes, topoisomerase inhibitors, vinca alkaloids, and miscellaneous agents.

[0304] Alkylating agents include altretamine, bendamustine, busulfan, carmustine, chlorambucil, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, procarbazine, streptozocin, temozolomide, thiotepa, and trabectedin.

[0305] Platinum coordination complexes include carboplatin, cisplatin, and oxaliplatin.

[0306] Cytotoxic antibiotics include bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin, mitoxantrone, plicamycin and valrubicin.

[0307] Antimetabolites include antifolates, such as methotrexate, pemetrexed, pralatrexate, and trimetrexate; purine analogs, such as azathioprine, cladribine, fludarabine, mercaptopurine, and thioguanine; and pyrimidine analogs, such as azacitidine, capecitabine, cytarabine, decitabine, floxiridine, fluorouracil, gemcitabine, and trifluridine / tipiracil.

[0308] Biological response modifiers include aldesleukin (IL-2), denileukin diftitox and interferon gamma.

[0309] Histone deacetylase inhibitors include belinostat, panobinostat, romidepsin and vorinostat.

[0310] Endocrine therapeutic agents (ie, hormone therapeutic agents) include antiandrogens, antiestrogens, gonadotropin releasing hormone (GnRH) analogs and peptide hormones. Examples of anti-estrogens include aromatase inhibitors, such as letrozole, anastrozole, and exemestane; SERDs, such as fulvestrant, elacestrant (RAD-1901, Radius Health / Menarini), amsenestrant (SAR439859, Sanofi), gildedestrant (GDC9545, Roche), RG6171 (Roche), camizestrant (AZD9833, AstraZeneca), AZD9496 (AstraZeneca), lindestrant (G1 Therapeutics), ZN-c5 (Zentalis), LSZ102 (Novartis), D-0502 (Inventisbio), LY3484356 (Eli Lilly), SHR9549 (Jiansu Hengrui Medicine); and SERMs, including, for example, tamoxifen, raloxifene, toremifene, lasofoxifene, bazedoxifene, and afimoxifene. Examples of GnRH analogs include degarelix, goserelin, histrelin, leuprolide, and triptorelin. Examples of peptide hormones include lanreotide, octreotide, and pasireotide. Examples of antiandrogens include abiraterone, apalutamide, bicalutamide, cyproterone, enzalutamide, flutamide, and nilutamide, as well as pharmaceutically acceptable salts and solvates thereof.

[0311] Monoclonal antibodies include alemtuzumab, atezolizumab, avelumab, bevacizumab, blinatumomab, brentuximab, cemiplimab, cetuximab, daratumumab, dinutuximab, durvalumab, elotuzumab, gemtuzumab, inotuzumab ozogamicin, ipilimumab, mogamulizumab, moxetumomab pasudotox, necitumumab, nivolumab, ofatumumab, olaratumumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, tositumomab, and trastuzumab.

[0312] Taxanes include cabazitaxel, docetaxel, paclitaxel and an albumin-stabilized nanoparticle formulation of paclitaxel.

[0313] Topoisomerase inhibitors include etoposide, irinotecan, teniposide and topotecan.

[0314] Vinca alkaloids include vinblastine, vincristine and vinorelbine, and pharma- ceutically acceptable salts thereof.

[0315] Miscellaneous antineoplastic agents include asparaginase (pegaspargase), bexarotene, eribulin, everolimus, hydroxyurea, ixabepilone, lenalidomide, mitotane, omacetaxine, pomalidomide, tagraxofusp, telotristat, temsirolimus, thalidomide, and venetoclax.

[0316] In some embodiments, the additional anticancer agent is abiraterone acetate; acalabrutinib; adotrastuzumab emtansine; afatinib dimaleate; affimoxifen; aldesleukin; alectinib; alemtuzumab; alpelisib; amifostine; anastrozole; apalutamide; aprepitant; arsenic trioxide; asparaginase Erwinia chrysanthemis chrysanthemi);atezolizumab;avapritinib;avelumab;axicabtadine ciloreucel;axitinib;azacitidine;AZD9833 (AstraZeneca);AZD9496 (AstraZeneca);bazedoxifene;belinostat;bendamustine hydrochloride;bevacizumab;bexarotene;bicalutamide;binimetinib;bleomycin sulfate;blinatumomab;bortezomib;bosutinib;brentuximab Vedotin;Brigatinib;Cabazitaxel;Cabozantinib-s-malate;Calaspargase pegol-mknl;Capecitabine;Caplacizumab-yhdp;Capmatinib hydrochloride;Carboplatin;Carfilzomib;Carmustine;Cemiplimab-rwlc;Ceritinib;Cetuximab;Chlorambucil;Cisplatin;Cladribine;Clofarabine;Cobimetinib;Copanlisib hydrochloride;Crizotinib;Cyclophosphamide;Cytarabine; D-0502 (Inventisbio); Dabrafenib mesylate; Dacarbazine; Dacomitinib; Dactinomycin; Daratumumab; Daratumumab and hyaluronidase-fihj; Darbepoetin alfa; Darolutamide; Dasatinib; Daunorubicin hydrochloride; Decitabine; Defibrotide sodium; Degarelix; Denileukin diftitox; Denosumab; Dexamethasone; Dexrazoxane hydrochloride; Dinutuximab; Docetaxel le;doxorubicin hydrochloride;durvalumab;duvelisib;elacestrant;elotuzumab;eltrombopagolamine;emapalumab-lzsg;enasidenib mesylate;encorafenib;enfortumab vedotin-ejfv;entrectinib;enzalutamide;epirubicin hydrochloride;epoetin alfa;erdafitinib;eribulin mesylate;erlotinib hydrochloride;etoposide;etoposide phosphate;everolimus;exemestane;fam-trastuzumab deruxtecan-nxki;fedratinib hydrochloride;filgrastim;fludarabine phosphate;fluorouracil;flutamide;fostamatinib disodium;fulvestrant;gefitinib;gemcitabine hydrochloride;gemtuzumab ozogamicin;gilteritinib fumarate;glasdegib maleate;glucarpidase;goserelin acetate;granisetron;granisetron hydrochloride;hydroxyurea;ibritumomab tiuxetan;ibrutinib;idarubicin hydrochloride;idelalisib;ifosfamide;imatinib mesylate ;Imiquimod;Inotuzumab ozogamicin;Interferon alpha-2b recombinant;Iobenguane I-131;Ipatasertib;Ipilimumab;Irinotecan hydrochloride;Isatuximab-irfc;Ivosidenib;Ixabepilone;Ixazomib citrate;Lanreotide acetate;Lapatinib ditosylate;Larotrectinib sulfate;Lasofoxifene;Lenalidomide;Lenvatinib mesylate;Letrozole;Leucovorin calcium;Leuprolide acetate;Lomustine;Lorlatinib;LSZ102 (Novartis);Lurbinectedi LY3484356 (Lilly);Megestrol acetate;Melphalan;Melphalan hydrochloride;Mercaptopurine;Methotrexate;Midostaurin;Mitomycin;Mitoxantrone hydrochloride;Mogamulizumab-kpkc;Moxetumomab-tdfk;Necitumumab;Nelarabine;Neratinib maleate;Nilotinib;Nilutamide;Niraparib tosilate monohydrate;Nivolumab;Obinutuzumab;Ofatumumab;Olaparib;Omacetaxine mepesuccinate;Ondansetron hydrochloride;Osimertinib mesylate;Oxa Liplatin;Paclitaxel;Paclitaxel albumin-stabilized nanoparticle formulation;Palifermin;Palonosetron hydrochloride;Pamidronate disodium;Panitumumab;Panobinostat;Pazopanib hydrochloride;Pegaspargase;Pegfilgrastim;Peginterferon alfa-2b;Pembrolizumab;Pemetrexed disodium;Pemigatinib;Pertuzumab;Pexidartinib hydrochloride;Plerixafor;Polatinib vedotin-piiq;Pomalidomide;Ponatinib hydrochloride;Pralatrexate;Prednisone;Procarbazine hydrochloride;Propranolol hydrochloride;Radium 223 dichloride;Raloxifene hydrochloride;Ramucirumab;Rasburicase;Ravulizumab-cwvz;Recombinant interferon alfa-2b;Regorafenib;RG6171 (Roche);Lintodestrant;Ripretinib;Rituximab;Rolapitant hydrochloride;Romidepsin;Romiplostim;Rucaparib camsilate;Ruxolitinib phosphate;Sacituzumab govitecan-hziy;SAR439859 (Sanofi);Selinexor;Selpercatinib;Selumetinib sulfate;SHR9549 (Jiansu Hengrui Medicine);Siltuximab;Sipuleucel-t;Sonidegib;Sorafenib tosilate;Tagraxofusp-erzs;Talazoparib tosilate;Talimogene laherparepvec;Tamoxifen citrate;Tazemetostat hydrobromide;Temozolomide;Temsirolimus;Thalidomide;Thioguanine;Thiotepa;Tisagenlecleucel;Tocilizumab;Topotecan hydrochloride;Toremifene;Trabectedin;Trametinib;Trastuzumab;Trastuzumab and hyaluronan The compound is selected from the group consisting of: dase-oysk; trifluridine and tipiracil hydrochloride; tucatinib; uridine triacetate; valrubicin; vandetanib; vemurafenib; venetoclax; vinblastine sulfate; vincristine sulfate; vinorelbine tartrate; vismodegib; vorinostat; zanubrutinib; ziv-aflibercept; ZN-c5 (Zentalis); and zoledronic acid; or a free base, pharma-ceutically acceptable salt or solvate form of the foregoing; or a combination thereof.

[0317] These and other aspects will become apparent from the teachings contained herein.

[0318] PF-07104091 may be prepared as described in US Pat. No. 11,014,911.

[0319] PF-07220060 may be prepared as described in US Pat. No. 10,766,884. EXAMPLES

[0320] The following examples are merely illustrative of the disclosure and should not be construed as limiting the scope of the invention, as these examples and other equivalents will be apparent to those of skill in the art in light of this disclosure and the appended claims.

[0321] Example 1 Spheroid growth inhibition NCI-H1792 and NCI-H23 lung adenocarcinoma (LUAD) cell lines were obtained from ATCC and maintained in RPMI160 medium supplemented with 10% fetal bovine serum and penicillin-streptomycin as per ATCC guidelines. Cells were maintained in a humidified incubator at 37°C and 5% CO2.

[0322] Spheroid assays were performed in 96-well ultra-low attachment plates (ULA-96U) from Nexcelom & Thermo Fisher Scientific. Two hundred (200) NCI-H1792 or NCI-H23 cells were dispensed into 200 μL of complete growth medium per well of each ultra-low attachment plate (n=10-12 wells per treatment group) to allow the formation of one spheroid per well with a diameter between 200-250 μm before treatment began (cell seeding numbers were pre-optimized so that the formed spheroids possessed this desired dimension). To support spheroid formation, dispensed cells were centrifuged at 220×g for 6 min in the ultra-low attachment plates to allow compact spheroids to form for 4 days before treatment began. After spheroids were formed, 150 μL of medium was aspirated from each well without disturbing the spheroids, and the same volume of fresh RPMI medium containing single agent compounds (palbociclib, PF-07220060, PF-07104091), or selected combinations thereof, was added. The final concentration of each compound in the well was 30 nM palbociclib; 300 nM PF-07220060 or PF-07104091. DMSO (0.01%) was used as a vehicle control. DMSO and all compounds were diluted in cell culture medium. Media and compounds were replenished twice a week at intervals of 3 and 4 days. Replenishment was performed by aspirating 150 μL of medium per well without disturbing the spheroids, and then adding the same volume of premixed media / compound solution to the spheroids. Spheroid diameter was quantified immediately after each medium change twice weekly (every 3 or 4 days) throughout the duration of the assay.

[0323] The mean diameter of tumor spheroids was plotted in GraphPad Prism 8 and AUC was calculated. AUC baseline was determined by the mean tumor spheroid diameter at day 0 in vehicle (DMSO) control. Spheroid growth inhibition or SGI was calculated as follows: SGI=(1-AUC treatment / AUC DMSO)×100%. SGI for all treatment arms was derived at the time when vehicle (DMSO) treated spheroids reached their maximum diameter (usually close to 1 mm, but this can vary between cell lines), which corresponds to the last time point obtained for vehicle (DMSO) treated spheroids. SEM was calculated based on n=10 to 12 wells per test group.

[0324] Growth of lung adenocarcinoma multicellular tumor spheroids (MCTS) was monitored over time to assess (i) the magnitude of response (SGI) and (ii) duration of response to the CDK4 inhibitor PF-07220060 as a single agent and in combination with the CDK2 inhibitor PF-07104091.

[0325] PF-07220060 and PF-07104091 are expected to reach a higher tolerated clinical exposure (due to reduced dose-limiting toxicity) than palbociclib (mean free plasma concentration of 30 nM) in humans. Therefore, spheroids were treated with PF-07220060 or PF-07104091 at 300 nM and compared to a clinically relevant concentration of palbociclib at 30 nM. PF-07104091 treatment sensitized NCI-H1792 and NCI-H23 spheroids to PF-07220060, indicating that the use of both agents in combination increases antitumor efficacy when compared to either compound alone. Moreover, 300 nM PF-07220060 plus 300 nM PF-07104091 showed superior spheroid growth inhibition when compared to 30 nM palbociclib plus 300 nM PF-07104091. Data are provided in Table 1.

[0326] [Table 1]

[0327] Example 2 Inhibition of proliferation of ER+ human breast cancer cells by PF-07104091 in combination with the CDK4 inhibitor PF-07220060 The combined effects of PF-07104091 and PF-07220060 were evaluated in cell proliferation assays using MCF7 and T47D BC cell lines. Each compound exhibited potent single-agent dose-dependent growth inhibition in both cell models.

[0328] The drug combination was determined based on the dose equivalence principle. Equivalence Principle and Loewe Volume The combinations were analyzed using the Loewe Volume score. When modeling synergy using the dose equivalence principle, the Loewe Volume score for the combination compound should be greater than the compound's self-cross control, and the Combination Index (CI) score for the combination compound should be less than the compound's self-cross control. The combination of PF-07104091 and PF-07220060 demonstrated a favorable profile for these two indices, Loewe Volume and CI, compared to the self-cross control in MCF7 breast cancer cell lines (Table 2) and T47D breast cancer cell lines (Table 3). Isobolograms set at a 70% anti-proliferative threshold supported the synergistic response. Based on the Loewe Volume, CI values, and isobolograms, moderate combination synergy was observed in these cell lines, with the highest benefit of the combination seen in the MCF7 model.

[0329] [Table 2]

[0330] [Table 3]

[0331] Example 3 Antitumor efficacy of PF-07104091 in combination with PF-07220060 in breast cancer tumor models method In vivo efficacy evaluation and statistical analysis A fragment (27 mm) was injected subcutaneously into the dorsum of a female NSG mouse (Jackson Lab). 3 From 64mm 3 Size) were implanted in the mice. For T47D, HCC1428 and ST941PBR studies, all mice were supplemented with 8.5 μg / mL estradiol water (β-estradiol Sigma-Aldrich, Cat. No. E2758-5G) and given ad libitum until the end of the study. For in vivo efficacy studies, tumor volume and body weight were measured twice weekly. Tumor volume was calculated using the formula [(length x width x width) / 2)]. TGI was calculated as 100 x (1-ΔT / ΔC). ΔC (ΔT) was obtained by subtracting the mean tumor burden in the vehicle (treated) group on the first day of treatment (day 0) from the mean tumor burden in the vehicle (treated) group on the day of assessment. Statistical analysis was performed using ANCOVA when the mean tumor volume in vehicle-treated mice reached the tumor cutoff size.

[0332] In vivo efficacy evaluation of PF-07104091 in combination with PF-07220060 or palbociclib in HR+ / HER2- T47D breast cancer models The T47D model was established by implanting third-passage tumor fragments into recipient mice. To establish T47D donor mice, tumor cells (5 × 10 6 700 to 800 mm 3 Once tumor volume reached 101 mm, the donor tumors were then transplanted into secondary recipient mice for expansion of the study. 3 From 255mm 3Once the tumor-bearing mice reached the range between 0.01 and 0.1% Tween 80 in water, they were randomly assigned to groups (n=8 per group) and dosed with 1) vehicle (0.5% MC plus 0.1% Tween 80 in water); 2) 150mg / kg PF-07104091; 3) 60mg / kg PF-07220060; 4) 10mg / kg PD-0332991; 5) 150mg / kg PF-07104091 plus 60mg / kg PF-07220060; 6) 150mg / kg PF-07104091 plus 10mg / kg palbociclib. PF-07104091 (Lot 016), PF-07220060 (Lot 019) and PD-0332991 (Lot GR08498) were administered (PO.) BID (every 7 hours). All mice continued to receive treatment until day 41. TGI was assessed on day 41 after the first dose.

[0333] In vivo efficacy evaluation of PF-07104091 in combination with PF-07220060 or palbociclib in the HR+ / HER2- HCC1428 breast cancer model The HCC1428 model was established by implanting 4th passage tumor fragments into recipient mice. To establish HCC1428 donor mice, tumor cells (5 × 10 6 700 to 800 mm 3 Once tumor volume reached 100 mm, donor tumors were then transplanted into secondary recipient mice for expansion of the study. 3 From 272mm 3Once the tumor-bearing mice reached the range between 0.01 and 0.10 mg / kg, tumor-bearing mice were randomly assigned to groups (n=10 per group) and dosed with 1) vehicle (0.5% MC plus 0.1% Tween 80 in water); 2) 150 mg / kg PF-07104091; 3) 60 mg / kg PF-07220060; 4) 10 mg / kg PD-0332991; 5) 150 mg / kg PF-07104091 plus 60 mg / kg PF-07220060; 6) 150 mg / kg PF-07104091 plus 10 mg / kg palbociclib. PF-07104091 (Lot 016), PF-07220060 (Lot 019) and PD-0332991 (Lot GR08498) were administered (PO.) BID (every 7 hours). All mice received treatment continuously through day 42. TGI was assessed on day 42 after the first dose.

[0334] Establishment of an in vivo palbociclib-acquired resistant HR+ / HER2-BC PDX model, ST941PBR The ST941PBR palbociclib-resistant model was obtained from XENOSTART™ LLC, San Antonio, Texas. We established the model in-house by continuous treatment of ST941PBR tumor-bearing mice with 50 mg / kg PD-0332991 PO QD, plus 10 mg / kg fulvestrant, SC, twice the first week, then weekly thereafter. The tumors were implanted into recipient mice to breed donors for TGI studies. One week after re-implantation, the recipient mice were subjected to continuous treatment with palbociclib plus fulvestrant (dosing schedule as described above). After 1 to 2 consecutive in vivo breedings using the same treatment regimen, the mice were cultured at 700 to 800 mm for study expansion. 3 Resistant tumors within the range of 100-200 μg / ml were re-embedded. The remaining tumor fragments were viably frozen for future use.

[0335] To demonstrate tolerance to treatment, ST941PBR tumor-bearing mice (p12) received palbociclib (50 mg / kg) plus fulvestrant (10 mg / kg) using the same treatment schedule described above.

[0336] In vivo efficacy evaluation of PF-07104091 in combination with PF-07220060 or palbociclib in the ST941PBR PDX model Viable donor mice were established by implanting ST941PBR(p11) tumor fragments. 3 Once tumor volume reached 121 mm, donor tumors were then transplanted into secondary recipient mice for study expansion. To maintain resistant clones, ST941PBR tumor-bearing mice were treated with 50 mg / kg PD-0332991, PO.QD, plus 10 mg / kg fulvestrant, SC, twice the first week, then weekly for the next 10 weeks. Treatment began 1 week after implantation and continued until the day of randomization for study enrollment. Tumor volume reached 121 mm 3 From 228mm 3 Once the range between 0.01 and 0.10 was reached, tumor-bearing mice were randomly assigned into groups (n=10 per group) and medicated with 1) vehicle (0.5% MC plus 0.1% Tween 80 in water); 2) 150 mg / kg PF-07104091; 3) 60 mg / kg PF-07220060; 4) 10 mg / kg PD-0332991; 5) 150 mg / kg PF-07104091 plus 60 mg / kg PF-07220060; 6) 150 mg / kg PF-07104091 plus 10 mg / kg palbociclib; 7) 10 mg / kg PD-0332991 plus 10 mg / kg fulvestrant; 8) 50 mg / kg PD-0332991 plus 10 mg / kg fulvestrant. PF-07104091 (Lot 016), PF-07220060 (Lot 019), PF-06873600 (Lot 022) and PD-0332991 (Lot GR08498) were administered (PO) BID (every 7 hours) at 10 mg / kg; PD-0332991 (Lot GR08498) was administered (PO) QD at 50 mg / kg and fulvestrant was administered SC twice the first week and then weekly thereafter. All mice received treatment continuously through day 28. TGI was assessed 28 days after the first dose.

[0337] Results and Discussion PF-07104091 was also evaluated as a single agent and in combination with palbociclib or PF-07220060 in three HR+, HER2-BC models: T47D, HCC1428, and palbociclib-resistant ST941PBR PDX. Treatment was administered PO, BID, at mg / kg (mpk) doses indicated in Table 4 (except for the 50 mg / kg QD palbociclib group and SC fulvestrant twice week 1 and weekly thereafter). There were no significant body weight changes or other notable clinical observations throughout the treatment period in any of the three models (no clinical pathology was performed).

[0338] In the T47D model, PF-07104091, PF-07220060 and palbociclib monotherapy showed significant TGI efficacy (p<0.05) versus vehicle. PF-07104091 plus PF-07220060 treatment showed significantly enhanced efficacy (TGI 106%) versus either PF-07220060 (TGI 73%) or PF-07104091 (TGI 82%) monotherapy (p<0.05 versus any of the 15 monotherapy). PF-07104091 plus palbociclib (TGI 100%) also showed significantly enhanced efficacy versus either monotherapy (p<0.05 versus any of the single therapy).

[0339] In the HCC1428 model, single-agent treatment with PF-07104091, PF-07220060, and palbociclib each also demonstrated significant TGI efficacy (p<0.05) versus vehicle.20PF-07104091 plus PF-07220060 treatment showed significantly enhanced efficacy (TGI 110%) versus either PF-07220060 (TGI 89%) or PF-07104091 (TGI 95%) monotherapy (Table 4).

[0340] In the palbociclib-resistant ST941PBR PDX model, palbociclib (10 mg / kg BID or 50 mg / kg QD) treatment in combination with fulvestrant showed a significant but marginal response (30% and 26% TGI vs. vehicle, respectively), supporting acquired resistance (Table 4). PF-07104091 in combination with palbociclib resulted in a significant TGI (49%) vs. vehicle or either PF-07104091 (TGI 34%) or palbociclib monotherapy. PF-07104091 treatment in combination with PF-07220060 significantly enhanced efficacy vs. either monotherapy (combined TGI of 98% vs. 34% for PF-07104091 monotherapy and 28% for PF-07220060 monotherapy). The combination of PF-07104091 plus PF-07220060 provided significantly improved benefit compared to the combination of PF-07104091 plus palbociclib in this palbociclib-resistant ST941PBRPDX model.

[0341] [Table 4]

[0342] Example 4 Antitumor efficacy of low-dose PF-07104091 in combination with PF-07220060 in breast cancer tumor models method In vivo efficacy evaluation and statistical analysis A fragment (27 mm) was injected subcutaneously into the dorsum of a female NSG mouse (Jackson Lab). 3 From 64mm 3Size) were implanted in the mice. For HCC1428, MCF7 and ST941PBR studies, all mice were supplemented with 8.5 μg / mL estradiol water (β-estradiol Sigma-Aldrich, Cat. No. E2758-5G) and given ad libitum until the end of the study. For in vivo efficacy studies, tumor volume and body weight were measured twice weekly. Tumor volume was calculated using the formula [(length x width x width) / 2)]. TGI was calculated as 100 x (1-ΔT / ΔC). ΔC (ΔT) was obtained by subtracting the mean tumor burden in the vehicle (treated) group on the first day of treatment (day 0) from the mean tumor burden in the vehicle (treated) group on the day of assessment. Statistical analysis was performed using ANCOVA when the mean tumor volume in vehicle-treated mice reached the tumor cutoff size.

[0343] In vivo efficacy evaluation of PF-07104091 in combination with PF-07220060 or palbociclib in the HR+ / HER2- HCC1428 breast cancer model The HCC1428 model was established by implanting first passage tumor fragments into recipient mice. To establish HCC1428 donor mice, tumor cells (5 × 10 6 700 to 800 mm 3 Once tumor volume reached 119 mm, donor tumors were subcutaneously implanted into secondary recipient mice for expansion of the study. 3 From 267mm 3Once the range between 0.01 and 0.10 was reached, tumor-bearing mice were randomly assigned to groups (n=10 per group) and dosed with 1) vehicle (0.5% MC plus 0.1% Tween 80 in water); 2) 120 mg / kg PF-07104091; 3) 60 mg / kg PF-07220060; 4) 30 mg / kg PF-06873600; 5) 10 mg / kg palbociclib plus 10 mg / kg fulvestrant; 6) 120 mg / kg PF-07104091 plus 20 mg / kg PF-07220060; 7) 75 mg / kg PF-07104091 plus 40 mg / kg PF-07220060; 8) 35 mg / kg PF-07104091 plus 60 mg / kg PF-07220060. PF-07104091 (Lot 022), PF-07220060 (Lot CPo126812-01-SY-5700-01), PF-06873600 (Lot 022) and PD-0332991 (Lot GR08498) were administered (PO) BID (every 7 hours) while 10 mg / kg Fulvestrant (Lot 20160224-2) was administered SC twice in the first week and then weekly thereafter. All mice received treatment continuously until day 42. TGI was assessed on day 42 after the first dose.

[0344] In vivo efficacy evaluation of PF-07104091 in combination with PF-07220060 or palbociclib in HR+ / HER2- MCF7 breast cancer models The MCF7 model was established by implanting donor tumor fragments into recipient mice. To establish MCF7 donor mice, tumor cells (5 × 10 6 700 to 800 mm 3 Once tumor volume reached 141 mm, the donor tumors were then transplanted into secondary recipient mice for expansion of the study. 3 From 231mm 3Once the range between 0.01 and 0.10 was reached, tumor-bearing mice were randomly assigned to groups (n=10 per group) and dosed with 1) vehicle (0.5% MC plus 0.1% Tween 80 in water); 2) 120 mg / kg PF-07104091; 3) 60 mg / kg PF-07220060; 4) 30 mg / kg PF-06873600; 5) 10 mg / kg palbociclib plus 10 mg / kg fulvestrant; 6) 120 mg / kg PF-07104091 plus 20 mg / kg PF-07220060; 7) 75 mg / kg PF-07104091 plus 40 mg / kg PF-07220060; 8) 35 mg / kg PF-07104091 plus 60 mg / kg PF-07220060. PF-07104091 (Lot 022), PF-07220060 (Lot CPo126812-01-SY-5700-01), PF-06873600 (Lot 022) and PD-0332991 (Lot GR08498) were administered (PO) BID (every 7 hours) while 10 mg / kg Fulvestrant (Lot 20160224-2) was administered SC twice in the first week and then weekly thereafter. All mice received treatment continuously until day 29. TGI was assessed on day 29 after the first dose.

[0345] Establishment of an in vivo palbociclib-acquired resistant HR+ / HER2-BC PDX model, ST941PBR The ST941PBR palbociclib-resistant model was obtained from XENOSTART™ LLC, San Antonio, Texas. We established the model in-house by continuous treatment of ST941PBR tumor-bearing mice with 50 mg / kg PD-0332991 PO QD, plus 10 mg / kg fulvestrant, SC, twice the first week, then weekly thereafter. The tumors were implanted into recipient mice to breed donors for TGI studies. One week after re-implantation, the recipient mice were subjected to continuous treatment with palbociclib plus fulvestrant (dosing schedule as described above). After 1 to 2 consecutive in vivo breedings using the same treatment regimen, the mice were cultured at 700 to 800 mm for study expansion. 3Resistant tumors within the range of 100-200 μg / ml were re-embedded. The remaining tumor fragments were viably frozen for future use.

[0346] To demonstrate tolerance to treatment, ST941PBR tumor-bearing mice (p14) received palbociclib (50 mg / kg) plus fulvestrant (10 mg / kg) using the same treatment schedule described above.

[0347] In vivo efficacy evaluation of PF-07104091 in combination with PF-07220060 or palbociclib in the ST941PBR PDX model Viable donor mice were established by implanting ST941PBR(p13) tumor fragments. 3 Once tumor volume reached 137 mm, donor tumors were then transplanted into secondary recipient mice for study expansion. To maintain resistant clones, ST941PBR tumor-bearing mice were treated with 50 mg / kg PD-0332991, PO.QD, plus 10 mg / kg fulvestrant, SC, twice the first week, then weekly for the next 10 weeks. Treatment began 1 week after implantation and continued until the day of randomization for study enrollment. Tumor volume reached 137 mm 3 From 216mm 3Once the range between 0.01 and 0.10 was reached, tumor-bearing mice were randomly assigned to groups (n=10 per group) and dosed with 1) vehicle (0.5% MC plus 0.1% Tween 80 in water); 2) 120 mg / kg PF-07104091; 3) 60 mg / kg PF-07220060; 4) 30 mg / kg PF-06873600; 5) 10 mg / kg palbociclib plus 10 mg / kg fulvestrant; 6) 120 mg / kg PF-07104091 plus 20 mg / kg PF-07220060; 7) 75 mg / kg PF-07104091 plus 40 mg / kg PF-07220060; 8) 35 mg / kg PF-07104091 plus 60 mg / kg PF-07220060. PF-07104091 (Lot 021), PF-07220060 (Lot CPo126812-01-SY-5700-01), PF-06873600 (Lot 022) and PD-0332991 (Lot GR08498) were administered (PO) BID (every 7 hours) while 10 mg / kg Fulvestrant (Lot 20160224-2) was administered SC twice the first week and then weekly thereafter. All mice received treatment continuously until day 28. TGI was assessed 28 days after the first dose.

[0348] Results and Discussion Lower dose levels of PF-07104091+PF-07220060 were also evaluated to test whether the combination could improve efficacy over monotherapy, PF-06873600 and SOC palbociclib+fulvestrant in three HR+, HER2-BC models: MCF7, HCC1428 and palbociclib-resistant ST941PBR PDX. Treatments were administered PO, BID, at mg / kg (mpk) doses indicated in Table 5 (except for 10 mg / kg SC fulvestrant twice week 1 and weekly thereafter). There were no significant body weight changes or other notable clinical observations throughout the treatment period in any of the three models (no clinical pathology was performed).

[0349] In the MCF7 model, SOC palbociclib 10 mg / kg + fulvestrant 10 mg / kg and single agent treatments of PF-07104091 at 120 mg / kg, PF-07220060 at 60 mg / kg, and PF-06873600 at 30 mg / kg demonstrated significant TGI efficacy versus vehicle (TGI 84%, 60%, 79% and 70%, respectively; p<0.05). The low dose PF-07104091 + PF-07220060 treatment groups - PF-4091 35mg / kg + PF-0060 60mg / kg, PF4091 75mg / kg + PF-0060 40mg / kg and PF-4091 120mg / kg + PF0060 20mg / kg showed significant regression (TGI 106%, 106%, 105%) compared to vehicle, SOC palbociclib 10mg / kg + fulvestrant 10mg / kg, and single agent treatments of PF-07104091 120mg / kg, PF-07220060 60mg / kg and PF-06873600 30mg / kg. There was also no significant efficacy difference between the low-dose PF-4091+PF-0060 groups (p>0.05) in the MCF7 model.

[0350] In the HCC1428 model, SOC palbociclib 10 mg / kg + fulvestrant 10 mg / kg and single agent treatments of PF-07104091 at 120 mg / kg, PF-07220060 at 60 mg / kg, and PF-06873600 at 30 mg / kg demonstrated significant TGI efficacy versus vehicle (TGI 70%, 79%, 70% and 97%, respectively; p<0.05). The low dose PF-07104091 + PF-07220060 treatment groups - PF-4091 35mg / kg + PF-0060 60mg / kg, PF4091 75mg / kg + PF-0060 40mg / kg and PF-4091 120mg / kg + PF0060 20mg / kg showed significant regressions (TGI 110%, 110%, 109%, respectively) compared to vehicle, SOC palbociclib 10mg / kg + fulvestrant 10mg / kg, and single agent treatments of PF-07104091 120mg / kg, PF-07220060 60mg / kg and PF-06873600 30mg / kg. There was also no significant efficacy difference between the low-dose PF-4091+PF-0060 groups (p>0.05) in the HCC1428 model.

[0351] In the palbociclib-resistant ST941PBR PDX model, palbociclib (10 mg / kg BID) treatment in combination with fulvestrant demonstrated a marginal response (14% TGI vs. vehicle), supporting acquired resistance (Table 5). PF-07220060 at 60 mg / kg demonstrated a marginal response (TGI 19%, p>0.05), and PF-07104091 at 120 mg / kg and PF-0873600 at 30 mg / kg demonstrated significant but moderate efficacy vs. vehicle (TGI 36% and 47%, respectively; p<0.05). The low dose PF-07104091 + PF-07220060 treatment groups - PF-4091 35mg / kg + PF-0060 60mg / kg, PF4091 75mg / kg + PF-0060 40mg / kg and PF-4091 120mg / kg + PF-0060 20mg / kg showed significant inhibition (TGI 87%, 98%, 94% respectively) compared to vehicle, SOC palbociclib 10mg / kg + fulvestrant 10mg / kg, and single agent treatments of PF-07104091 at 120mg / kg, PF-07220060 at 60mg / kg and PF-06873600 at 30mg / kg. Among the low-dose groups, there was no significant efficacy difference between PF-4091 75mg / kg + PF-0060 40mg / kg and PF-4091 120mg / kg + PF-0060 20mg / kg, but there was a significant difference between PF-4091 75mg / kg + PF-0060 40mg / kg and PF-4091 120mg / kg + PF-0060 20mg / kg (p<0.05) versus PF-4091 35mg / kg + PF-0060 60mg / kg.

[0352] Results demonstrate the ability to lower exposure to either agent or both and maintain maximal tumor control (regression in study) in cell line models of primary disease (MCF7 and HCC1428). In the therapy-resistant model STR941-PBR, lowering the CDK2i dose in the combination regimen to 35mg BID differentiated it from other combination groups tested, demonstrating a slightly lower TGI and more robust recovery from treatment in the study.

[0353] [Table 5]

[0354] Example 5 Activity of the combination of PF-07104091 and PF-07220060 in lung adenocarcinoma The activity of the combination of PF-07104091 and PF-07220060 was evaluated in LUAD as single agents (sa) or in combination. Data are provided in Table 6.

[0355] [Table 6]

[0356] Example 6 Preliminary Drug-Drug Interaction (DDI) Risk Assessment A preliminary substrate / victim DDI risk assessment for PF-07104091 was performed using a static mechanistic model with clinically relevant concentrations of PF-07220060 (Fahmi OA, Hurst S, Plowchalk D, et al. Comparison of different algorithms for predicting clinical drug-drug interactions, based on the use of CYP3A4 in vitro data: predictions of compounds as precipitants of interaction. Drug Metab Dispos 2009;37(8):1658-66).

[0357] Based on the potential combination dose (75 mg PF-07104091 plus 300 mg PF-07220060), PF-07220060 was predicted to exhibit potential addendum-based cytochrome P450 3A (CYP3A) time-dependent inhibition (TDI) versus combined PF-07104091, resulting in an AUC ratio (AUCR) of approximately 2.

[0358] Other than potential CYP3A DDIs, there are no additional data indicating a significant DDI risk between PF-07104091 and PF-07220060, both as inflictors and substrates / victims, at clinically relevant concentrations, and the addition of letrozole or fulvestrant to this combination.

[0359] Example 7 A Phase 1b / 2, open-label, multicenter, randomized, dose-escalation and dose-expansion study to evaluate the safety, tolerability, PK, PD, and antitumor activity of PF-07220060 administered in combination with PF-07104091 A Phase 1b / 2, open-label, multicenter, randomized, dose-escalation and dose-expansion study to evaluate the safety, tolerability, PK, PD, and antitumor activity of PF-07220060 and PF-07104091 (doublet combination) in participants with metastatic breast cancer (mBC) or other advanced solid tumors (Part 1), and in participants with metastatic / advanced mBC (Part 2) when the doublet combination is administered with endocrine therapy (ET). As of the data cut-off date, 12 participants across four dose cohorts had received the doublet combination therapy (dose escalation) in Part 1.

[0360] In Part 2, each of the two triple combinations (PF-07220060, PF-07104091 and fulvestrant, or PF-07220060, PF-07104091 and letrozole) will enroll a safety run-in of approximately six participants to establish the safety and tolerability of the combination. Part 2A will include participants previously treated with a CDK4 / 6 inhibitor, who will receive the triple combination of PF-07220060, PF-07104091 and fulvestrant. Part 2B will include participants who are treatment-naive to CDK4 / 6 inhibitors but previously treated with one ET, who will receive the triple combination of PF-07220060, PF-07104091 and fulvestrant. Part 2C includes participants who are treatment-naive to CDK4 / 6 inhibitors and ET for progressive disease, who will receive the triple combination of PF-07220060, PF-07104091 and letrozole.

[0361] Dose escalation of PF-07220060 and PF-07104091 will continue in a stepwise fashion according to the Bayesian logistic regression model (BLRM) recommendations. Dose escalation will continue until the MTD of the PF-07220060 and PF-07104091 combination is determined or stopping criteria for further escalation are met. The highest doses of PF-07220060 and PF-07104091 tested in this study will not be higher than the monotherapy MTD / recommended dose for expansion (RDE) of each drug as determined from the monotherapy studies, respectively. Dose escalation decisions will also take into account all available clinical data from this study.

[0362] Enriched PK sampling of both PF-07220060 and PF-07104091 will be performed to assess PK and DDI potential. To assess potential DDI, Part 1 participants will receive a single dose of PF-07104091 on Day 1 with PK assessments up to 24 hours after dosing of PF-07104091. Participants initially on Day 1 of Cycle 1 will receive both PF-07220060 and PF-07104091 on a continuous schedule given as a BID regimen, with PK assessments after multiple doses assessed on Day 15 of Cycle 1. PK assessments may be modified (e.g., removal of Day 1 assessments of Cycle 1) based on evolutionary data from initial cohorts in DDI assessments.

[0363] Part 1 will enroll participants with metastatic / advanced breast cancer and other advanced or metastatic solid tumors with no standard alternative treatment options to determine the two-agent MTD / RDE. Each cohort will enroll approximately 2 to 4 participants. At least 6 participants will be treated with the recommended combination doses of PF-07220060 and PF-07104091 prior to the initiation of dose expansion.

[0364] Participants with BC may also receive fulvestrant after at least 2 cycles of the combination of PF-07220060 and PF-07104091, at the investigator's discretion and with sponsor approval if: · The current doses of PF-07220060 and PF-07104091 that participants are receiving as combination therapy have been determined to be safe by the BLRM; · Participants have not experienced any adverse events (AEs) that meet DLT criteria, or; The AE meeting the DLT criteria has been resolved and the participant has resumed PF-07220060 and PF-07104091 combination therapy for at least 28 days without an AE meeting the DLT criteria.

[0365] Part 2 (dose expansion) will enroll up to three cohorts of participants with advanced or metastatic HR-positive, HER2-negative BC treated with the triple combination of PF-07220060, PF-07104091 and ET (letrozole or fulvestrant). Part 2A includes participants who have been previously treated with a CDK4 / 6 inhibitor. Part 2B includes participants who are CDK4 / 6 inhibitor naïve but have been previously treated with one form of ET. · Part 2C includes participants who are treatment-naive to CDK4 / 6 inhibitors and ET for progressive disease.

[0366] Participants in parts 2A and 2B will be treated with the triplet of PF-07220060, PF-07104091 and fulvestrant starting in cycle 1, and participants in part 2C will be treated with the triplet of PF-07220060, PF-07104091 and letrozole starting in cycle 1.

[0367] A dose escalation or de-escalation approach at full or intermediate dose levels of PF-07220060 or PF-07104091 will be utilized depending on emerging clinical data to select the combination RDE. BLRM will be used in part 1 with EWOC criteria to determine the MTD.

[0368] All cycles will be 28 days long and treatment will continue until disease progression, uncontrollable toxicity, participant or investigator decision to discontinue treatment, or end of study. Participants experiencing toxicity, including DLTs, may be managed by dose modification or interruption from either PF-07220060 or PF-07104091 treatment, or both.

[0369] PF-07220060 and PF-07104091 are administered orally BID with continuous daily dosing. Alternative dosing regimens, schedules and PK time points may be considered based on emerging PK data, safety, tolerability, laboratory and PD to allow optimal dosing regimens of PF-07220060 and PF-07104091 in combination with endocrine therapy, i.e., letrozole or fulvestrant.

[0370] As of the data cut-off date, a total of 12 participants across four dose cohorts had previously received PF-07220060 in combination with PF-07104091 (a selective CDK2 inhibitor) in part 1 (dose escalation).

[0371] demographics Overall, a total of 12 participants (11 females and 1 male) with a mean age of 55.25 years (SD: 11.19) received PF-07220060 + PF-07104091. Participants had advanced cancers including HR+HER2- breast cancer (n=8), small cell carcinoma (n=1), ovarian (n=1), small cell lung cancer (n=1) and unreported (n=1).

[0372] Treatment-emergent all-cause adverse events Of the 12 treated participants, 10 (83.3%) participants reported a total of 88 treatment-emergent adverse events (TEAEs).

[0373] The most frequently reported (≥20%) all-cause events were nausea (58.3%), diarrhea, neutropenia and leukopenia (50.0% each), anemia (41.7%), lymphopenia (33.3%), fatigue, thrombocytopenia, and vomiting (25.0% each).

[0374] No grade 4 TEAEs were reported. One grade 5 TEAE, disease progression, was reported during the study.

[0375] Treatment-emergent treatment-related adverse events A total of 10 of the 12 participants (83.3%) reported treatment-related TEAEs.

[0376] The most commonly reported (≥20%) treatment-related AEs were nausea (58.3%), diarrhea, neutropenia and leukopenia (50.0% each), lymphopenia (33.3%), anemia, fatigue, thrombocytopenia, and vomiting (25.0% each).

[0377] No grade 4 or 5 treatment-related TEAEs were reported during the study.

[0378] Dose-limiting toxicity As of the data cutoff date, one DLT (grade 3 fatigue) was reported in one participant receiving PF-07220060 300 mg BID + PF-07104091 150 mg BID.

[0379] Adverse events leading to discontinuation No participants discontinued study medication due to adverse events.

[0380] Serious Adverse Events and Deaths No serious adverse events (SAEs) or deaths related to study treatment were reported. One participant in the PF-07220060 200 mg BID + PF-07104091 75 mg BID treatment group in Part 1 reported an SAE of dyspnea. Another participant in the PF-07220060 300 mg BID + PF-07104091 150 mg BID treatment group in Part 1 reported an SAE of disease progression resulting in death. None of the SAEs were related to study treatment.

Claims

1. A compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt or solvate thereof, wherein R １ is -L-(5- to 6-membered heteroaryl) or -L-(phenyl), wherein said 5- to 6-membered heteroaryl or phenyl is selected from 1 to 3 R ３ and optionally substituted by R ２ is C １ ~C ６ Alkyl or C ３ ~C ７ cycloalkyl, wherein said C ３ ~C ７ Cycloalkyl is C １ ~C ４ optionally substituted by alkyl, L is a bond or methylene; Each R ３ are independently １ ~C ４ Alkyl, C １ ~C ４ Alkoxy or SO ２ -C １ ~C ４ alkyl, where each C １ ~C ４ Alkyl is F, OH or C １ ~C ４ 1. A pharmaceutical composition for use in a method of treating cancer in a subject, comprising: (a) an amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and (b) an amount of a compound of formula (II): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, R ４ is H, F or Cl, R ５ is H, C １ ~C ５ Alkyl, C １ ~C ５ Fluoroalkyl or C ３ ~C ８ cycloalkyl, wherein each C １ ~C ５ Alkyl and C １ ~C ５ Fluoroalkyl is R ８ and each of said C ３ ~C ８ Cycloalkyl is R ９ and optionally substituted by R ６ is H, C １ ~C ４ Alkyl or C １ ~C ４ fluoroalkyl, wherein each C １ ~C ４ Alkyl and C １ ~C ４ Fluoroalkyl is R ８ and optionally substituted by R ７ is H, F or Cl, Each R ８ are independently OH, C １ ~C ４ Alkoxy or NR １０ R １１ and Each R ９ are independently F, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy or NR １０ R １１ and Each R １０ and R １１ are independently H or C １ ~C ２ alkyl] administering wherein the amounts of (a) and (b) together are effective to treat cancer. Pharmaceutical compositions.

2. The pharmaceutical composition of claim 1, wherein the method for treating cancer further comprises the step of administering to the subject (c) an amount of an additional anticancer agent, wherein the amounts of (a), (b) and (c) are together effective to treat cancer.

3. 3. The pharmaceutical composition of claim 2, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, bladder cancer, colon cancer, uterine cancer, prostate cancer, esophageal cancer, liver cancer, pancreatic cancer and gastric cancer.

4. 4. The pharmaceutical composition of claim 3, wherein the cancer is hormone receptor-positive (HR+) breast cancer and the additional anticancer agent is an endocrine therapeutic agent selected from the group consisting of an aromatase inhibitor, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD).

5. 5. The pharmaceutical composition of claim 4, wherein the endocrine therapeutic agent is letrozole or fulvestrant.

6. 2. The pharmaceutical composition of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentylpropan-2-ylcarbamate (PF-07104091) monohydrate.

7. The pharmaceutical composition described in claim 6, wherein the amount of PF-07104091 administered to the subject in the method for treating cancer is from about 75 mg to about 500 mg BID.

8. The pharmaceutical composition described in claim 7, wherein the amount of PF-07104091 administered to the subject is approximately 75 mg BID, approximately 150 mg BID, or approximately 225 mg BID.

9. 2. The pharmaceutical composition of claim 1, wherein the compound of formula (II) is 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (PF-07220060), or a pharmaceutically acceptable salt thereof.

10. 10. The pharmaceutical composition of claim 9, wherein the amount of PF-07220060 is from about 100 mg to about 500 mg BID.

11. 11. The pharmaceutical composition of claim 10, wherein the amount of PF-07220060 is about 100 mg BID, about 200 mg BID, or about 300 mg BID.

12. A compound of formula (II): 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, R 4 is H, F or Cl; R 5 is H, C 1 -C 5 alkyl, C 1 -C 5 fluoroalkyl or C 3 -C 8 cycloalkyl, wherein each said C 1 -C 5 alkyl and C 1 -C 5 fluoroalkyl is optionally substituted by R 8 , and each said C 3 -C 8 cycloalkyl is optionally substituted by R 9 ; R 6 is H, C 1 -C 4 alkyl or C 1 -C 4 fluoroalkyl, wherein each of said C 1 -C 4 alkyl and C 1 -C 4 fluoroalkyl is optionally substituted by R 8 ; R 7 is H, F or Cl; each R 8 is independently OH, C 1 -C 4 alkoxy, or NR 10 R 11 ; each R 9 is independently F, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or NR 10 R 11 ; each R 10 and R 11 is independently H or C 1 -C 2 alkyl; (a) an amount of a compound of formula (I): 【Transformation 3】 or a pharmaceutically acceptable salt or solvate thereof, wherein R １ is -L-(5- to 6-membered heteroaryl) or -L-(phenyl), wherein said 5- to 6-membered heteroaryl or phenyl is selected from 1 to 3 R ３ and optionally substituted by R ２ is C １ ~C ６ Alkyl or C ３ ~C ７ cycloalkyl, wherein said C ３ ~C ７ Cycloalkyl is C １ ~C ４ optionally substituted by alkyl, L is a bond or methylene; Each R ３ are independently １ ~C ４ Alkyl, C １ ~C ４ Alkoxy or SO ２ -C １ ~C ４ alkyl, where each C １ ~C ４ Alkyl is F, OH or C １ ~C ４ optionally substituted by alkoxy; and (b) a compound of formula (II) or a pharmaceutically acceptable salt thereof administering wherein the amounts of (a) and (b) together are effective to treat cancer. Pharmaceutical compositions.

13. The pharmaceutical composition of claim 12, wherein the method for treating cancer further comprises administering to the subject (c) an amount of an additional anticancer agent, wherein the amounts of (a), (b) and (c) are together effective to treat cancer.

14. 14. The pharmaceutical composition of claim 13, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, bladder cancer, colon cancer, uterine cancer, prostate cancer, esophageal cancer, liver cancer, pancreatic cancer and gastric cancer.

15. 15. The pharmaceutical composition of claim 14, wherein the cancer is hormone receptor positive (HR+) breast cancer and the additional anticancer agent is an endocrine therapeutic agent selected from the group consisting of an aromatase inhibitor, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD).

16. 16. The pharmaceutical composition of claim 15, wherein the endocrine therapeutic agent is letrozole or fulvestrant.

17. 13. The pharmaceutical composition of claim 12, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentylpropan-2-ylcarbamate (PF-07104091) monohydrate.

18. 18. The pharmaceutical composition of claim 17, wherein the amount of PF-07104091 is from about 50 mg to about 250 mg BID.

19. 19. The pharmaceutical composition of claim 18, wherein the amount of PF-07104091 is about 75 mg BID, about 150 mg BID, or about 225 mg BID.

20. 13. The pharmaceutical composition of claim 12, wherein the compound of formula (II) is 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol (PF-07220060), or a pharmaceutically acceptable salt thereof.

21. The pharmaceutical composition of claim 20, wherein the amount of PF-07220060 administered to the subject in the method for treating cancer is from about 100 mg to about 500 mg BID.

22. The pharmaceutical composition of claim 21, wherein the amount of PF-07220060 administered to the subject is about 100 mg BID, about 200 mg BID, or about 300 mg BID.

23. The pharmaceutical composition described in claim 1 or 12, wherein the cancer is a palbociclib-resistant cancer.

24. The pharmaceutical composition described in claim 1 or 12, wherein the subject has previously been treated with a CDK4 / 6 inhibitor.

25. The pharmaceutical composition described in claim 24, wherein the CDK4 / 6 inhibitor is palbociclib.

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