Targeted treatment of cancer with deregulated fibroblast growth factor receptor signaling

Abstract

The present invention provides advantageous methods and compositions for treating a host having a cancer with dysregulated FGFR signal transduction pathway comprising administering an effective amount of a selective CDK4 / 6 inhibitor described herein in combination or alternately with a fibroblast growth factor receptor inhibitor.

Description

[0001] This application is a divisional application of Chinese Invention Patent Application No. 202080084419.3, filed on October 9, 2020, with the title of “Targeted Therapy of Cancer with Dysregulated Fibroblast Growth Factor Receptor Signaling”.

[0002] Related Applications

[0003] This application is related to and claims priority from U.S. Provisional Application No. 62 / 913,055, filed on October 9, 2019. The entire contents of this provisional application are incorporated herein by reference for all purposes. TECHNICAL FIELD

[0004] The present invention provides compositions employing a CDK4 / 6 inhibitor in combination with a fibroblast growth factor inhibitor (e.g., a selective FGFR-tyrosine kinase inhibitor) for the treatment of cancer with dysregulated fibroblast growth factor receptor (FGFR) signaling, wherein the particular combination provides a favorable or synergistic inhibitory activity, delays the acquisition of resistance to the inhibitory effect of the FGFR inhibitor in the cancer, and / or extends the efficacy of the FGFR inhibitor. BACKGROUND

[0005] The fibroblast growth factor receptors belong to a family of four tyrosine kinases (FGFR1-4) and a fifth receptor lacking a tyrosine kinase domain (FGFR5) (Hallinan N, Finn S, Cuffe S, Rafee S, O'Byrne K, Gately K. Targeting the fibroblast growth factor receptor family in cancer. Cancer Treat Rev 2016; 46: 51-62, Wesche J, Haglund K, Haugsten EM. Fibroblast growth factors and their receptors in cancer. Biochem J 2011; 437: 199-213). FGFRs have been shown to regulate many key processes such as cell migration, proliferation, differentiation and survival, particularly during embryonic development and in adult organisms during inflammation and wound healing (Hallinan N, Finn S, Cuffe S, Rafee S, O'Byrne K, Gately K. Targeting the fibroblast growth factor receptor family in cancer. Cancer Treat Rev 2016; 46: 51-62, Wesche J, Haglund K, Haugsten EM. Fibroblast growth factors and their receptors in cancer. Biochem J 2011; 437: 199-213). FGFR activity is controlled by a family of 22 FGF members (Touat M, Ileana E, Postel-Vinay S, Andre F, Soria JC. Targeting FGFR Signaling in Cancer. Clin Cancer Res 2015; 21: 2684-94) that regulate FGFR tyrosine kinase activity in an autocrine or paracrine tissue-dependent context (Itoh N, Ornitz DM. Functional evolutionary history of the mouse Fgf gene family. Dev Dyn 2008; 237: 18-27).Cancers such as breast cancer, lung cancer, gastric cancer, urothelial cancer, and liver cancer (e.g., intrahepatic cholangiocarcinoma and hepatocellular carcinoma) have FGFR signaling pathway overactivation due to oncogenic abnormalities in FGFR family members or due to FGF overproduction leading to FGFR overactivation, although the nature of the oncogenic alterations can differ for each cancer type.

[0006] Fibroblast growth factor receptors (FGFRs) are membrane-bound proteins that regulate cellular functions, including cell proliferation, cell survival, differentiation, and migration (Brooks AN, Kilgour E, Smith PD. Molecular pathways: fibroblast growth factor signaling: a new therapeutic opportunity in cancer. Clin Cancer Res 2012; 18: 1855-62). Activation of the FGFR family (FGFR1, FGFR2, FGFR3, and FGFR4) leads to increased downstream activation of oncogenic pathways such as MAPK and AKT (Babina IS, Turner NC. Advances and challenges in targeting FGFR signaling in cancer. Nat Rev Cancer 2017; 17: 318-32). Amplification, mutation, and aberrant fusion of FGFR genes lead to constitutive activation of these pathways downstream signaling, enhancing cell growth and migration (Dienstmann R, Patnaik A, Garcia-Carbonero R, Cervantes A, Benavent M, et al. Safety and activity of the first-in-class Sym004 anti-EGFR antibody mixture in patients with refractory colorectal cancer. Cancer Discov 2015; 5: 598-609). In addition, FGFR activation due to FGF overproduction from the expansion of cancer and stromal cells is associated with aberrant FGFR signaling (see, e.g., Zhang et al., Targeting the Oncogenic FGF-FGFR Axis in Gastric Carcinogenesis. Cells 2019, 8, 637; doi:10.3390 / cells8060637).

[0007] Emerging clinical data from various FGFR inhibitors have confirmed FGFR as a potential target for anticancer therapy. The first FGFR inhibitors evaluated clinically were non-selective, such as brinanib, dovirtinib, and panatinib, whose on-target and off-target activities may contribute to clinical response. More recently, selective FGFR inhibitors, such as infelgratinib (BGJ398), have shown encouraging antitumor activity in clinical trials. In fact, in a phase I dose-escalation trial, six confirmed partial responses were observed in patients with FGFR1-amplified squamous NSCLC and FGFR3-mutant urothelial carcinoma using ≥100 mg of infligratinib (Isaacs, Randi and Chen, Xueying and Graus Porta, Diana and Parker, Katie and Yu, Kun and Porter, Dale (2018) Efficacy of BGJ398, a fibroblast growth factor receptor (FGFR) 1-3 inhibitor, in patients with previously treated advanced urothelial carcinoma with FGFR3 alterations. Cancer discovery. ISSN 2159-8290; 2159-8274).

[0008] Other orally available selective pan-FGFR inhibitors have been described, including: deratinib (ARQ-087, Arqule) (Hall TG, Yu Y, Eathiraj S, Wang Y, Savage RE, et al., Preclinical activity of ARQ 087, a novel inhibitor targeting FGFR dysregulation. PLoS One 2016; 11:e0162594); AZD4547 (AstraZeneca) (Gavine PR, Mooney L, Kilgour E, Thomas AP, Al-Kadhimi K, et al., AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res 2012; 72:2045-56); and infelgratinib (BGJ398, Novartis) (Guagnano V, Kauffmann A, et al., S, Stamm C, Ito M, etc., FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective Pan-FGFR inhibitor. Cancer Discov 2012; 2: 1118 - 33); erdafitinib (JNJ-42756493, Janssen) (Perera TPS, Jovcheva E, Mevellec L, Vialard J, De Lange D, etc., Discovery and pharmacological characterization of JNJ-42756493 (erdafitinib), a functionally selective small-molecule FGFR family inhibitor. Mol Cancer Ther 2017; 16: 1010 - 20); futibatinib (TAS-120; Taiho) (Kalyukina M, Yosaatmadja Y, Middleditch MJ, Patterson AV, Smaill JB, etc., TAS-120 cancer target binding: defining reactivity and revealing the first fibroblast growth factor receptor 1 (FGFR1) irreversible structure. ChemMedChem 2019; 14: 494 - 500); and pemigatinib (INCB054828, InCyte) (Hollebecque A, Lihou C, Zhen H, Abou-Alfa GK, Borad M, etc., Interim results of fight-202, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with previously treated advanced / metastatic or surgically unresectable cholangiocarcinoma (CCA) with / without fibroblast growth factor (FGF) / FGF receptor (FGFR) genetic alterations.(Ann Oncol 2018; 29). These targeted and selective FGFR inhibitors specifically target the kinase domains that activate the FGFR protein and have progressed from preclinical trials to early-stage clinical trials. Initial clinical trials demonstrating antitumor activity in urothelial carcinoma and intrahepatic cholangiocarcinoma with dysregulated FGFR pathway signaling have led to larger-scale confirmatory clinical trials and regulatory approvals.

[0009] For example, erdatinib (BALVERSA; Janssen Biotech) is a selective and potent pan-FGFR 1–4 inhibitor that, based on in vitro data, binds to and inhibits the enzymatic activity of FGFR1, FGFR2, FGFR3, and FGFR4. Erdatinib has been shown to inhibit FGFR phosphorylation and signal transduction, and to reduce cell viability in cell lines expressing altered FGFR genes, including point mutations, amplifications, and fusions. Erdatinib has also demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types including bladder cancer.

[0010] Erdatinib has recently been approved for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) who are: 1) susceptible to FGFR3 or FGFR2 gene alterations, and 2) have progressed during or after at least one prior platinum-based chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-based chemotherapy.

[0011] Pemitinib (PEMAZYRE; Incyte Corp.) has recently been approved for the treatment of adult patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma who have fibroblast growth factor receptor 2 (FGFR2) fusions or other rearrangements. Clinical trials have shown an overall response rate of 36% and a median duration of response of 9.1 months with pemitinib monotherapy.

[0012] Despite the clinical benefits of these FGFR-targeted therapies, prolonged exposure to the drugs can lead to the potential acquisition of resistance. This secondary refractory period typically results from the accumulation of novel genetic alterations at the kinase target, in other receptor tyrosine kinases (RTKs), or in molecules acting downstream of these RTKs (Camidge DR, Pao W, Sequist LV; Acquired resistance to TKIs in solid tumors: learning from lung cancer. Nat RevClin Oncol. 2014 Aug; 11(8):473-81; Lau et al., Mechanisms of acquired resistance to fibroblast growth factor receptor targeted therapy. Cancer Drug Resist 2019; 2:568-579). Acquired genetic alterations can be de novo or as clonal expansion of pre-existing low-abundance clones in the tumor. The mechanisms of FGFR resistance are diverse, including activation of alternative receptor tyrosine kinases, induction of alternative cell signaling pathways, induction of epithelial-mesenchymal transition, and the emergence of gatekeeper mutations such as FGFR1 V561M substitution, FGFR2 V565I, N550K, or V564 substitution, and FGFR3 V555M substitution (see, for example, Zhou et al., FGF / FGFR signaling pathway involved resistance in various cancer types. J Cancer. 2020; 11(8):2000–2007). Resistance to FGFR inhibitors limits their effectiveness and ability to promote long-term inhibition.

[0013] One object of the present invention is to provide compositions, uses, combinations and methods for preparing medicines thereof, which effectively target cancers having dysregulation of the FGFR signaling pathway due to FGFR or FGF abnormalities, and effectively reduce or delay the development of acquired resistance to FGFR inhibitors targeting FGFR signaling dysregulation, and have a treatment regimen capable of long-term administration.

[0014] This invention also relates to the following items:

[0015] 1. A method of treating a host with non-small cell lung cancer, said non-small cell lung cancer having dysregulation of the fibroblast growth factor receptor (FGFR) signaling pathway caused by an abnormality of FGFR1 or FGFR2, said abnormality being selected from the group consisting of overexpression, amplification, translocation, fusion, or mutation, said method comprising administering to the host an effective amount of a short-acting CDK4 / 6 inhibitor and administering to the host an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI), said CDK4 / 6 inhibitor being...

[0016]

[0017] Where R is N×X, and X is hydrogen, methyl, or isopropyl.

[0018] Or its pharmaceutically acceptable salt.

[0019] 2. The method described in Project 1, wherein the host is a human being.

[0020] 3. The method described in Project 2, wherein the non-small cell lung cancer has FGFR1 amplification or FGFR1 overexpression.

[0021] 4. The method described in Project 2, wherein the non-small cell lung cancer has FGFR2 amplification and FGFR2 overexpression.

[0022] 5. The method of any one of items 1 to 4, wherein the non-small cell lung cancer is large cell lung cancer.

[0023] 6. The method of any one of items 1 to 4, wherein the non-small cell lung cancer is squamous cell carcinoma.

[0024] 7. The method of any one of items 1 to 6, wherein the selective FGFR-TKI is selected from the following: erdatinib, pemitinib, inflistatinib, fabatinib, deratinib, LY287445, Debio1347, PRN1371, alonib, bemarituzumab, GSK3052230, and FIIN-2.

[0025] 8. The method of any one of items 1 to 7, wherein the CDK4 / 6 inhibitor is:

[0026] Or its pharmaceutically acceptable salt.

[0027] 9. The method of any one of items 1 to 7, wherein the CDK4 / 6 inhibitor is

[0028]

[0029] 10. The method of Item 9, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2° and 22.4±0.2°.

[0030] 11. The method of any one of items 1 to 7, wherein the CDK4 / 6 inhibitor has the following structure:

[0031] Or its pharmaceutically acceptable salt.

[0032] 12. The method of any one of items 1 to 11, wherein the CDK4 / 6 inhibitor and the FGFR inhibitor are administered to the host at least once daily for at least 28 consecutive days.

[0033] 13. The method of any one of items 1 to 11, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 35 consecutive days.

[0034] 14. The method of any one of items 1 to 11, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 56 consecutive days.

[0035] 15. The method of any one of items 1 to 14, wherein the host has not received CDK4 / 6 inhibitor treatment at the time of the first administration of the CDK4 / 6 inhibitor.

[0036] 16. The method of any one of items 1 to 15, wherein, at the time of the first administration of the CDK4 / 6 inhibitor, the cancer has acquired resistance to one or more previously administered FGFR inhibitors.

[0037] 17. The method of any one of items 1 to 16, wherein the cancer has acquired a mutation that makes it susceptible to developing resistance to one or more FGFR-TKIs at the time of the first administration of the CDK4 / 6 inhibitor.

[0038] 18. A method for reducing the development of acquired resistance to the inhibitory effects of a selective FGFR-TKI in a host with non-small cell lung cancer exhibiting an FGFR1 or FGFR2 abnormality, wherein the FGFR1 or FGFR2 abnormality is selected from the group consisting of overexpression, amplification, translocation, fusion, or mutation, the method comprising administering an effective amount of a short-acting CDK4 / 6 inhibitor to the host, and administering an effective amount of a selective FGFR-TKI to the host, wherein the CDK4 / 6 inhibitor is:

[0039]

[0040] Where R is N×X, and X is hydrogen, methyl, or isopropyl.

[0041] Or its pharmaceutically acceptable salt.

[0042] 19. The method described in item 18, wherein the host is a human being.

[0043] 20. The method of any one of items 18 to 19, wherein the FGFR1 abnormality or FGFR2 abnormality is overexpression or amplification.

[0044] 21. The method of any one of items 18 to 20, wherein the non-small cell lung cancer is large cell lung cancer.

[0045] 22. The method of any one of items 18 to 20, wherein the non-small cell lung cancer is squamous cell carcinoma.

[0046] 23. The method of any one of items 18 to 22, wherein the selective FGFR-TKI is selected from the following: erdatinib, pemitinib, inflistatinib, fabatinib, deratinib, LY287445, Debio1347, PRN1371, alonib, bemarituzumab, GSK3052230, and FIIN-2.

[0047] 24. The method of any one of items 18 to 23, wherein the CDK4 / 6 inhibitor is:

[0048] Or its pharmaceutically acceptable salt.

[0049] 25. The method of any one of items 18 to 23, wherein the CDK4 / 6 inhibitor is

[0050]

[0051] 26. The method of Item 25, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2° and 22.4±0.2°.

[0052] 27. The method of any one of items 18 to 23, wherein the CDK4 / 6 inhibitor has the following structure:

[0053] Or its pharmaceutically acceptable salt.

[0054] 28. The method of any one of items 18 to 27, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 28 consecutive days.

[0055] 29. The method of any one of items 18 to 27, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 35 consecutive days.

[0056] 30. The method of any one of items 18 to 27, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 56 consecutive days.

[0057] 31. The method of any one of items 18 to 30, wherein the host has not received CDK4 / 6 inhibitor treatment at the time of the first administration of the CDK4 / 6 inhibitor.

[0058] 32. The method of any one of items 18 to 31, wherein the cancer has acquired resistance to one or more previously administered FGFR inhibitors at the time of the first administration of the CDK4 / 6 inhibitor.

[0059] 33. The method of any one of items 18 to 32, wherein the cancer has acquired a mutation that makes it susceptible to developing resistance to one or more FGFR-TKIs at the time of the first administration of the CDK4 / 6 inhibitor.

[0060] 34. A method for treating a host with gastric adenocarcinoma, said gastric adenocarcinoma having dysregulation of the FGFR signaling pathway caused by FGFR2 abnormality, said abnormality being selected from the group consisting of: overexpression, amplification, translocation, fusion, or mutation, said method comprising administering an effective amount of a short-acting CDK4 / 6 inhibitor to the host, and administering an effective amount of a selective FGFR-TKI to the host, said CDK4 / 6 inhibitor being...

[0061]

[0062] Where R is N×X, and X is hydrogen, methyl, or isopropyl.

[0063] Or its pharmaceutically acceptable salt.

[0064] 35. The method described in item 34, wherein the host is a human being.

[0065] 36. The method described in item 34 or 35, wherein the FGFR2 abnormality is the result of FGFR2 overexpression or amplification.

[0066] 37. The method of any one of items 34 to 36, wherein the selective FGFR-TKI is selected from the following: erdatinib, pemitinib, inflistatinib, fabatinib, deratinib, LY287445, Debio1347, PRN1371, alonib, bemarituzumab, and FIIN-2.

[0067] 38. The method of any one of items 34 to 37, wherein the CDK4 / 6 inhibitor is:

[0068] Or its pharmaceutically acceptable salt.

[0069] 39. The method of any one of items 34 to 37, wherein the CDK4 / 6 inhibitor is

[0070]

[0071] 40. The method of items 34 to 37, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5 ± 0.2°, 9.5 ± 0.2°, 14.0 ± 0.2°, 14.4 ± 0.2°, 18.1 ± 0.2°, 19.9 ± 0.2°, and 22.4 ± 0.2°.

[0072] 41. The method of any one of items 34 to 37, wherein the CDK4 / 6 inhibitor has the following structure:

[0073] Or its pharmaceutically acceptable salt.

[0074] 42. The method of any one of items 34 to 41, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 28 consecutive days.

[0075] 43. The method of any one of items 34 to 41, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 35 consecutive days.

[0076] 44. The method of any one of items 34 to 41, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 56 consecutive days.

[0077] 45. The method of any one of items 34 to 44, wherein the host has not received CDK4 / 6 inhibitor treatment at the time of the first administration of the CDK4 / 6 inhibitor.

[0078] 46. ​​The method of any one of items 34 to 45, wherein the cancer has acquired resistance to one or more previously administered FGFR inhibitors at the time of the first administration of the CDK4 / 6 inhibitor.

[0079] 47. The method of any one of items 34 to 46, wherein the cancer has acquired a mutation that makes it susceptible to developing resistance to one or more FGFR-TKIs at the time of the first administration of the CDK4 / 6 inhibitor.

[0080] 48. A method for reducing the development of acquired resistance to the inhibitory effect of a selective FGFR-TKI in a host with gastric adenocarcinoma exhibiting an FGFR2 abnormality, wherein the abnormality is selected from the group consisting of overexpression, amplification, translocation, fusion, or mutation, the method comprising administering an effective amount of a short-acting CDK4 / 6 inhibitor to the host, and administering an effective amount of a selective FGFR-TKI to the host, wherein the CDK4 / 6 inhibitor is:

[0081]

[0082] Where R is N×X, and X is methyl or isopropyl.

[0083] Or its pharmaceutically acceptable salt.

[0084] 49. The method described in item 48, wherein the host is a human being.

[0085] 50. The method of any one of items 48 to 49, wherein the FGFR abnormality is FGFR overexpression or amplification.

[0086] 51. The method of any one of items 48 to 50, wherein the selective FGFR-TKI is selected from the following: erdatinib, pemitinib, inflistatinib, fabatinib, deratinib, LY287445, Debio1347, PRN1371 and FIIN-2.

[0087] 52. The method of any one of items 48 to 51, wherein the CDK4 / 6 inhibitor is:

[0088] Or its pharmaceutically acceptable salt.

[0089] 53. The method of any one of items 48 to 51, wherein the CDK4 / 6 inhibitor is

[0090]

[0091] 54. The method of Item 53, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2° and 22.4±0.2°.

[0092] 55. The method of any one of items 48 to 51, wherein the CDK4 / 6 inhibitor has the following structure:

[0093] Or its pharmaceutically acceptable salt.

[0094] 56. The method of any one of items 48 to 55, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 28 consecutive days.

[0095] 57. The method of any one of items 48 to 55, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 35 consecutive days.

[0096] 58. The method of any one of items 48 to 55, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 56 consecutive days.

[0097] 59. The method of any one of items 48 to 58, wherein the host has not received CDK4 / 6 inhibitor treatment at the time of the first administration of the CDK4 / 6 inhibitor.

[0098] 60. The method of any one of items 48 to 59, wherein, at the time of the first administration of the CDK4 / 6 inhibitor, the cancer has acquired resistance to one or more previously administered FGFR inhibitors.

[0099] 61. The method of any one of items 48 to 60, wherein the cancer has acquired a mutation that makes it susceptible to developing resistance to one or more FGFR-TKIs at the time of the first administration of the CDK4 / 6 inhibitor.

[0100] 62. A method of treating a host with cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by FGFR1 amplification or overexpression, the method comprising administering an effective amount of a short-acting CDK4 / 6 inhibitor to the host, and administering an effective amount of a selective FGFR-TKI to the host, wherein the CDK4 / 6 inhibitor is

[0101]

[0102] Where R is NX, and X is hydrogen, methyl, or isopropyl, or a pharmaceutically acceptable salt thereof.

[0103] The cancers mentioned therein are selected from the following: non-small cell lung cancer, small cell lung cancer, triple-negative breast cancer, osteosarcoma, pilocytic astrocytoma, and glioblastoma.

[0104] 63. The method described in item 62, wherein the host is a human being.

[0105] 64. The method of any one of items 62 to 63, wherein the selective FGFR-TKI is selected from the following: erdatinib, pemitinib, inflistatinib, fabatinib, deratinib, Debio1347, PRN1371, FIIN2, GSK3052230 and PD173074.

[0106] 65. The method of any one of items 62 to 64, wherein the CDK4 / 6 inhibitor is:

[0107] Or its pharmaceutically acceptable salt.

[0108] 66. The method of any one of items 62 to 64, wherein the CDK4 / 6 inhibitor is

[0109]

[0110] 67. The method of Item 66, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5 ± 0.2°, 9.5 ± 0.2°, 14.0 ± 0.2°, 14.4 ± 0.2°, 18.1 ± 0.2°, 19.9 ± 0.2°, and 22.4 ± 0.2°.

[0111] 68. The method of any one of items 62 to 64, wherein the CDK4 / 6 inhibitor has the following structure:

[0112] Or its pharmaceutically acceptable salt.

[0113] 69. The method of any one of items 62 to 68, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 28 consecutive days.

[0114] 70. The method of any one of items 62 to 68, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 35 consecutive days.

[0115] 71. The method of any one of items 62 to 68, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 56 consecutive days.

[0116] 72. The method of any one of items 62 to 71, wherein the host has not received CDK4 / 6 inhibitor treatment at the time of the first administration of the CDK4 / 6 inhibitor.

[0117] 73. The method of any one of items 62 to 72, wherein the cancer has acquired resistance to one or more previously administered FGFR inhibitors at the time of the first administration of the CDK4 / 6 inhibitor.

[0118] 74. The method of any one of items 62 to 73, wherein the cancer has acquired a mutation that makes it susceptible to developing resistance to one or more FGFR-TKIs at the time of the first administration of the CDK4 / 6 inhibitor.

[0119] 75. A method of treating a host with cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by FGFR2 abnormality, wherein the FGFR2 abnormality is selected from the group consisting of FGFR2 amplification or overexpression, FGFR2 mutation, and FGFR2 translocation or fusion, the method comprising administering an effective amount of a short-acting CDK4 / 6 inhibitor to the host, and administering an effective amount of a selective FGFR-TKI to the host, wherein the CDK4 / 6 inhibitor is

[0120]

[0121] Where R is NX, and X is methyl or isopropyl, or a pharmaceutically acceptable salt thereof.

[0122] The cancers mentioned therein are selected from the following: endometrial cancer, non-small cell lung cancer, gastric cancer, intrahepatic bile duct cancer, and thyroid cancer.

[0123] 76. The method described in item 75, wherein the host is a human being.

[0124] 77. The method described in item 77, wherein the FGFR2 abnormality is FGFR2 amplification or overexpression.

[0125] 78. The method of any one of items 75 to 77, wherein the selective FGFR-TKI is selected from the following: erdatinib, pemitinib, inflistatinib, fabatinib, deratinib, LY287445, Debio1347, PRN1371, alonib, bemarituzumab, and FIIN-2.

[0126] 79. The method of any one of items 75 to 78, wherein the CDK4 / 6 inhibitor is:

[0127] Or its pharmaceutically acceptable salt.

[0128] 80. The method of any one of items 75 to 78, wherein the CDK4 / 6 inhibitor is

[0129]

[0130] 81. The method of Item 80, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2° and 22.4±0.2°.

[0131] 82. The method of any one of items 75 to 78, wherein the CDK4 / 6 inhibitor has the following structure:

[0132] Or its pharmaceutically acceptable salt.

[0133] 83. The method of any one of items 75 to 82, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 28 consecutive days.

[0134] 84. The method of any one of items 75 to 82, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 35 consecutive days.

[0135] 85. The method of any one of items 75 to 82, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 56 consecutive days.

[0136] 86. The method of any one of items 75 to 85, wherein the host has not received CDK4 / 6 inhibitor treatment at the time of the first administration of the CDK4 / 6 inhibitor.

[0137] 87. The method of any one of items 75 to 86, wherein the cancer has acquired resistance to one or more previously administered FGFR inhibitors at the time of the first administration of the CDK4 / 6 inhibitor.

[0138] 88. The method of any one of items 75 to 87, wherein the cancer has acquired a mutation that makes it susceptible to developing resistance to one or more FGFR-TKIs at the time of the first administration of the CDK4 / 6 inhibitor.

[0139] 89. A method of treating a host with cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by FGFR3 abnormality, wherein the FGFR3 abnormality is selected from the group consisting of FGFR3 amplification or overexpression, FGFR3 mutation, and FGFR3 translocation or fusion, the method comprising administering an effective amount of a short-acting CDK4 / 6 inhibitor to the host, and administering an effective amount of a selective FGFR-TKI to the host, wherein the CDK4 / 6 inhibitor is

[0140]

[0141] Where R is NX, and X is hydrogen, methyl, or isopropyl, or a pharmaceutically acceptable salt thereof.

[0142] The cancers mentioned therein are selected from the following: glioblastoma, non-small cell lung cancer, cervical cancer, and multiple myeloma.

[0143] 90. The method described in Item 89, wherein the FGFR3 anomaly is an FGFR3 translocation or fusion.

[0144] 91. The method of any one of items 89 to 90, wherein the selective FGFR-TKI is selected from the following: erdatinib, pemitinib, inflistatinib, fabatinib, deratinib, LY287445, Debio1347, PRN1371, MGFR1877S, vorvastatinib, and FIIN-2.

[0145] 92. The method of any one of items 89 to 91, wherein the CDK4 / 6 inhibitor is:

[0146] Or its pharmaceutically acceptable salt.

[0147] 93. The method of any one of items 89 to 91, wherein the CDK4 / 6 inhibitor is

[0148]

[0149] 94. The method of Item 93, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2° and 22.4±0.2°.

[0150] 95. The method of any one of items 89 to 91, wherein the CDK4 / 6 inhibitor has the following structure:

[0151] Or its pharmaceutically acceptable salt.

[0152] 96. The method of any one of items 89 to 95, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 28 consecutive days.

[0153] 97. The method of any one of items 89 to 95, wherein the CDK4 / 6 inhibitor and the EGFR-TKI are administered to the host at least once daily for at least 35 consecutive days.

[0154] 98. The method of any one of items 89 to 95, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 56 consecutive days.

[0155] 99. The method of any one of items 89 to 99, wherein the host has not received CDK4 / 6 inhibitor treatment at the time of the first administration of the CDK4 / 6 inhibitor.

[0156] 100. The method of any one of items 89 to 99, wherein the cancer has acquired resistance to one or more previously administered FGFR inhibitors at the time of the first administration of the CDK4 / 6 inhibitor.

[0157] 101. The method of any one of items 89 to 100, wherein the cancer has acquired a mutation that makes it susceptible to developing resistance to one or more FGFR-TKIs at the time of the first administration of the CDK4 / 6 inhibitor.

[0158] 102. A method of treating a host with cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by FGFR4 abnormality or FGF abnormality, wherein the FGFR4 abnormality is selected from the group consisting of FGFR4 amplification, FGFR4 mutation, and FGFR4 translocation, and the FGF abnormality is overexpression or amplification, the method comprising administering an effective amount of a short-acting CDK4 / 6 inhibitor to the host, and administering an effective amount of a selective fibroblast growth factor receptor (FGFR) inhibitor to the host, wherein the CDK4 / 6 inhibitor is

[0159]

[0160] Where R is NX, and X is methyl or isopropyl, or a pharmaceutically acceptable salt thereof.

[0161] The cancers mentioned therein are selected from the following: hepatocellular carcinoma, rhabdomyosarcoma, endometrial cancer, and ovarian cancer.

[0162] 103. The method described in item 102, wherein the host is a human being.

[0163] 104. The method of any one of items 102 to 103, wherein the selective FGFR inhibitor is selected from the following: infelterinib, fabatinib, deratinib, LY287445, INCB062079, BLU9931, H3-6527, fexotinib, robrutinib, Debio1347, PRN1371 and FIIN-2.

[0164] 105. The method of any one of items 102 to 104, wherein the CDK4 / 6 inhibitor is:

[0165] Or its pharmaceutically acceptable salt.

[0166] 106. The method of any one of items 102 to 104, wherein the CDK4 / 6 inhibitor is

[0167]

[0168] 107. The method of Item 106, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2° and 22.4±0.2°.

[0169] 108. The method of any one of items 102 to 104, wherein the CDK4 / 6 inhibitor has the following structure:

[0170] Or its pharmaceutically acceptable salt.

[0171] 109. The method of any one of items 102 to 108, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 28 consecutive days.

[0172] 110. The method of any one of items 102 to 108, wherein the CDK4 / 6 inhibitor and the FGFR inhibitor are administered to the host at least once daily for at least 35 consecutive days.

[0173] 111. The method of any one of items 102 to 108, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 56 consecutive days.

[0174] 112. The method of any one of items 102 to 111, wherein the host has not received CDK4 / 6 inhibitor treatment at the time of the first administration of the CDK4 / 6 inhibitor.

[0175] 113. The method of any one of items 102 to 112, wherein the cancer has acquired resistance to one or more previously administered FGFR inhibitors at the time of the first administration of the CDK4 / 6 inhibitor.

[0176] 114. The method of any one of items 102 to 113, wherein the cancer has acquired a mutation that makes it susceptible to developing resistance to one or more FGFR-TKIs at the time of the first administration of the CDK4 / 6 inhibitor.

[0177] 115. A short-acting CDK4 / 6 inhibitor compound of the following formula:

[0178]

[0179] Where R is N×X, and X is hydrogen, methyl, or isopropyl.

[0180] Or a pharmaceutically acceptable salt thereof, for the treatment of a host with non-small cell lung cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by an abnormal mutation in FGFR1 or FGFR2, wherein said abnormality is selected from the following: overexpression, amplification, translocation, fusion, or mutation, including administration of an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administration of an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0181] 116. A short-acting CDK4 / 6 inhibitor compound of the following formula:

[0182]

[0183] Where R is N×X, and X is hydrogen, methyl, or isopropyl.

[0184] Or a pharmaceutically acceptable salt thereof, for the purpose of reducing the development of resistance to the inhibitory effects of selective FGFR-TKIs in hosts with non-small cell lung cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by an abnormal mutation in FGFR1 or FGFR2, wherein the abnormality is selected from the group consisting of overexpression, amplification, translocation, fusion, or mutation, including administration of an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administration of an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0185] 117. A short-acting CDK4 / 6 inhibitor compound of the following formula:

[0186]

[0187] Where R is N×X, and X is hydrogen, methyl, or isopropyl.

[0188] Or a pharmaceutically acceptable salt thereof, for treating a host with gastric adenocarcinoma having a dysregulated FGFR signaling pathway caused by an FGFR2 abnormality, wherein the abnormality is selected from the following: overexpression, amplification, translocation, fusion, or mutation, comprising administering an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administering an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0189] 118. A short-acting CDK4 / 6 inhibitor compound of the following formula:

[0190]

[0191] Where R is N×X, and X is hydrogen, methyl, or isopropyl.

[0192] Or a pharmaceutically acceptable salt thereof, for treating a host with gastric adenocarcinoma having an FGFR2 abnormality, wherein the abnormality is selected from the following: overexpression, amplification, translocation, fusion, or mutation, comprising administering an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administering an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0193] 119. A short-acting CDK4 / 6 inhibitor compound of the following formula:

[0194]

[0195] Where R is N×X, and X is hydrogen, methyl, or isopropyl.

[0196] Or a pharmaceutically acceptable salt thereof, for treating a host with cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by FGFR1 amplification or overexpression, comprising administering to the host an effective amount of the short-acting CDK4 / 6 inhibitor and administering to the host an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI).

[0197] 120. A short-acting CDK4 / 6 inhibitor compound of the following formula:

[0198]

[0199] Where R is N×X, and X is hydrogen, methyl, or isopropyl.

[0200] Or a pharmaceutically acceptable salt thereof, for treating a host with cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by an FGFR2 abnormality selected from the following: FGFR2 amplification or overexpression, FGFR2 mutation, and FGFR2 translocation or fusion, comprising administering an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administering an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0201] 121. A short-acting CDK4 / 6 inhibitor compound of the following formula:

[0202]

[0203] Where R is N×X, and X is hydrogen, methyl, or isopropyl.

[0204] Or a pharmaceutically acceptable salt thereof, for treating a host with cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by an FGFR3 abnormality selected from the following: FGFR3 amplification or overexpression, FGFR3 mutation, and FGFR3 translocation or fusion, comprising administering an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administering an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0205] 122. A short-acting CDK4 / 6 inhibitor compound of the following formula:

[0206]

[0207] Where R is N×X, and X is hydrogen, methyl, or isopropyl.

[0208] Or a pharmaceutically acceptable salt thereof, for treating a host with cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by an FGFR4 abnormality or an FGF abnormality, wherein the FGFR4 abnormality is selected from the group consisting of FGFR4 amplification, FGFR4 mutation, and FGFR4 translocation, and wherein the FGF abnormality is overexpression or amplification, comprising administering an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administering an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0209] 123. The compositions described in items 115 to 122, wherein the host is a human being.

[0210] 124. The composition of any one of items 115 to 123, wherein the selective FGFR-TKI is selected from the following: erdatinib, pemitinib, inflistatinib, fabatinib, deratinib, LY287445, Debio1347, PRN1371, alonib, bemarituzumab, GSK3052230, FIIN-2, INCB062079, BLU9931, H3-6527, fexotinib, and robutinib.

[0211] 125. The composition of any one of items 115 to 124, wherein the CDK4 / 6 inhibitor is:

[0212] Or its pharmaceutically acceptable salt.

[0213] 126. The composition of any one of items 115 to 124, wherein the CDK4 / 6 inhibitor is

[0214]

[0215] 127. The composition of item 126, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2° and 22.4±0.2°.

[0216] 128. The composition of any one of items 115 to 124, wherein the CDK4 / 6 inhibitor has the following structure:

[0217] Or its pharmaceutically acceptable salt.

[0218] 129. The composition of any one of items 115 to 128, wherein the CDK4 / 6 inhibitor and the FGFR inhibitor are administered to the host once daily for at least 28 consecutive days.

[0219] 130. The composition of any one of items 115 to 128, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 35 consecutive days.

[0220] 131. The composition of any one of items 115 to 128, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 56 consecutive days.

[0221] 132. The composition of any one of items 115 to 131, wherein the host has not received CDK4 / 6 inhibitor treatment at the time of the first administration of the CDK4 / 6 inhibitor.

[0222] 133. The composition of any one of items 115 to 132, wherein, at the time of the first administration of the CDK4 / 6 inhibitor, the cancer has acquired resistance to one or more previously administered FGFR inhibitors.

[0223] 134. The composition of any one of items 115 to 133, wherein the cancer has acquired a mutation at the time of the first administration of the CDK4 / 6 inhibitor, making the cancer susceptible to developing resistance to one or more FGFR-TKIs.

[0224] 135. Short-acting CDK4 / 6 inhibitor compounds of the following formula:

[0225]

[0226] Wherein R is NX, and where X is hydrogen, methyl, or isopropyl, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a host with non-small cell lung cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by an abnormal mutation in FGFR1 or FGFR2, wherein the abnormality is selected from the following: overexpression, amplification, translocation, fusion, or mutation, including administration of an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administration of an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0227] 136. Short-acting CDK4 / 6 inhibitor compounds of the following formula:

[0228]

[0229] Wherein R is NX, and where X is hydrogen, methyl, or isopropyl, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for reducing the development of resistance to the inhibitory effect of a selective FGFR-TKI in a host with non-small cell lung cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by an abnormal mutation in FGFR1 or FGFR2, wherein the abnormality is selected from the group consisting of overexpression, amplification, translocation, fusion, or mutation, including administration of an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administration of an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0230] 137. Short-acting CDK4 / 6 inhibitor compounds of the following formula:

[0231]

[0232] Wherein R is NX, and where X is hydrogen, methyl, or isopropyl, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a host with gastric adenocarcinoma having a dysregulated FGFR signaling pathway caused by an FGFR2 abnormality, wherein the abnormality is selected from the following: overexpression, amplification, translocation, fusion, or mutation, including administration of an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administration of an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0233] 138. Short-acting CDK4 / 6 inhibitor compounds of the following formula:

[0234]

[0235] Wherein R is NX, and where X is hydrogen, methyl, or isopropyl, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a host with gastric adenocarcinoma caused by an FGFR 2 abnormality, wherein the abnormality is selected from the following: overexpression, amplification, translocation, fusion, or mutation, including administration of an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administration of an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0236] 139. The following short-acting CDK4 / 6 inhibitor compound:

[0237]

[0238] Wherein R is NX, and where X is hydrogen, methyl, or isopropyl, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a host with cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by FGFR1 amplification or overexpression, comprising administering to the host an effective amount of the short-acting CDK4 / 6 inhibitor and administering to the host an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI).

[0239] 140. Short-acting CDK4 / 6 inhibitor compounds of the following formula:

[0240]

[0241] Wherein R is NX, and where X is hydrogen, methyl, or isopropyl, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a host with cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by an FGFR2 abnormality, wherein the FGFR2 abnormality is selected from the following: FGFR2 amplification or overexpression, FGFR2 mutation, and FGFR2 translocation or fusion, comprising administering an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administering an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0242] 141. Short-acting CDK4 / 6 inhibitor compounds of the following formula:

[0243]

[0244] Wherein R is NX, and where X is hydrogen, methyl, or isopropyl, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a host with cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by an FGFR3 abnormality, wherein the FGFR3 abnormality is selected from the following: FGFR3 amplification or overexpression, FGFR3 mutation, and FGFR3 translocation or fusion, comprising administering an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administering an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0245] 142. Short-acting CDK4 / 6 inhibitor compounds of the following formula:

[0246]

[0247] Wherein R is NX, and where X is hydrogen, methyl, or isopropyl, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a host with cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by an FGFR4 abnormality or an FGF abnormality, wherein the FGFR4 abnormality is selected from the group consisting of FGFR4 amplification, FGFR4 mutation, and FGFR4 translocation, and the FGF abnormality is overexpression or amplification, comprising administering an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administering an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0248] 143. The compositions described in items 135 to 142, wherein the host is a human being.

[0249] 144. The use of any one of items 135 to 143, wherein the selective FGFR-TKI is selected from the following: erdatinib, pemitinib, inflistatinib, fabatinib, deratinib, LY287445, Debio1347, PRN1371, alonib, bemarituzumab, GSK3052230, FIIN-2, INCB062079, BLU9931, H3-6527, fexotinib, and robutinib.

[0250] 145. The composition of any one of items 135 to 144, wherein the CDK4 / 6 inhibitor is:

[0251] Or its pharmaceutically acceptable salt.

[0252] 146. The use of any one of items 135 to 144, wherein the CDK4 / 6 inhibitor is

[0253]

[0254] 147. The use described in item 146, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2° and 22.4±0.2°.

[0255] 148. Use of any one of items 135 to 143, wherein the CDK4 / 6 inhibitor has the following structure:

[0256] Or its pharmaceutically acceptable salt.

[0257] 149. The use of any one of items 135 to 148, wherein the CDK4 / 6 inhibitor and the FGFR inhibitor are administered to the host at least once daily for at least 28 consecutive days.

[0258] 150. The use of any one of items 135 to 148, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 35 consecutive days.

[0259] 151. The use of any one of items 135 to 148, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 56 consecutive days.

[0260] 152. The use of any one of items 135 to 151, wherein the host has not received CDK4 / 6 inhibitor treatment at the time of the first administration of the CDK4 / 6 inhibitor.

[0261] 153. The use of any one of items 135 to 152, wherein, at the time of the first administration of the CDK4 / 6 inhibitor, the cancer has acquired resistance to one or more previously administered FGFR inhibitors.

[0262] 154. Use of any one of items 135 to 153, wherein the cancer has acquired a mutation at the time of the first administration of the CDK4 / 6 inhibitor, making the cancer susceptible to developing resistance to one or more FGFR-TKIs.

[0263] 155. Short-acting CDK4 / 6 inhibitor compounds of the following formula:

[0264]

[0265] The use of R, where R is NX, and X is hydrogen, methyl, or isopropyl, or a pharmaceutically acceptable salt thereof, for the treatment of a host with non-small cell lung cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by an abnormal mutation in FGFR1 or FGFR2, wherein the abnormality is selected from the following: overexpression, amplification, translocation, fusion, or mutation, wherein the treatment comprises administering to the host an effective amount of the short-acting CDK4 / 6 inhibitor and administering to the host an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI).

[0266] 156. Short-acting CDK4 / 6 inhibitor compounds of the following formula:

[0267]

[0268] Wherein R is NX, and where X is hydrogen, methyl, or isopropyl, or a pharmaceutically acceptable salt thereof, for the purpose of reducing the development of acquired resistance to the inhibitory effect of a selective FGFR-TKI in a host with non-small cell lung cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by an abnormal mutation in FGFR1 or FGFR2, wherein the abnormality is selected from the group consisting of overexpression, amplification, translocation, fusion, or mutation, including administration of an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administration of an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0269] 157. Short-acting CDK4 / 6 inhibitor compounds of the following formula:

[0270]

[0271] Wherein R is NX, and where X is hydrogen, methyl, or isopropyl, or a pharmaceutically acceptable salt thereof, for the treatment of a host with gastric adenocarcinoma having a dysregulated FGFR signaling pathway caused by an FGFR2 abnormality, wherein the abnormality is selected from the following: overexpression, amplification, translocation, fusion, or mutation, including administration of an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administration of an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0272] 158. Short-acting CDK4 / 6 inhibitor compounds of the following formula:

[0273]

[0274] Wherein R is NX, and where X is hydrogen, methyl, or isopropyl, or a pharmaceutically acceptable salt thereof, for the purpose of treating a host with gastric adenocarcinoma having an FGFR2 abnormality, wherein the abnormality is selected from the following: overexpression, amplification, translocation, fusion, or mutation, including administration of an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administration of an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0275] 159. Short-acting CDK4 / 6 inhibitor compounds of the following formula:

[0276]

[0277] The use of R, where R is NX, and where X is hydrogen, methyl, or isopropyl, or a pharmaceutically acceptable salt thereof, for treating a host with cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by FGFR1 amplification or overexpression, comprising administering to the host an effective amount of the short-acting CDK4 / 6 inhibitor and administering to the host an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI).

[0278] 160. Short-acting CDK4 / 6 inhibitor compounds of the following formula:

[0279]

[0280] The use of R, where R is NX, and X is hydrogen, methyl, or isopropyl, or a pharmaceutically acceptable salt thereof, for treating a host with cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by an FGFR2 abnormality selected from the group consisting of FGFR2 amplification or overexpression, FGFR2 mutation, and FGFR2 translocation or fusion, including administration of an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administration of an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0281] 161. Short-acting CDK4 / 6 inhibitor compounds of the following formula:

[0282]

[0283] The use of R, where R is NX, and X is hydrogen, methyl, or isopropyl, or a pharmaceutically acceptable salt thereof, for treating a host with cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by an FGFR3 abnormality selected from the following: FGFR3 amplification or overexpression, FGFR3 mutation, and FGFR3 translocation or fusion, comprising administering an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administering an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0284] 162. Short-acting CDK4 / 6 inhibitor compounds of the following formula:

[0285]

[0286] The use of R, where R is NX, and X is hydrogen, methyl, or isopropyl, or a pharmaceutically acceptable salt thereof, for treating a host with cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by an FGFR4 abnormality or an FGF abnormality, wherein the FGFR4 abnormality is selected from the group consisting of FGFR4 amplification, FGFR4 mutation, and FGFR4 translocation, and the FGF abnormality is overexpression or amplification, comprising administering an effective amount of the short-acting CDK4 / 6 inhibitor to the host, and administering an effective amount of a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) to the host.

[0287] 163. The compositions described in items 155 to 162, wherein the host is a human being.

[0288] 164. The use of any one of items 155 to 163, wherein the selective FGFR-TKI is selected from the following: erdatinib, pemitinib, inflistatinib, fabatinib, deratinib, LY287445, Debio1347, PRN1371, alonib, bemarituzumab, GSK3052230, FIIN-2, INCB062079, BLU9931, H3-6527, fexotinib, and robutinib.

[0289] 165. The composition of any one of items 155 to 164, wherein the CDK4 / 6 inhibitor is:

[0290] Or its pharmaceutically acceptable salt.

[0291] 166. The use of any one of items 155 to 164, wherein the CDK4 / 6 inhibitor is

[0292]

[0293] 167. The use described in item 166, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2° and 22.4±0.2°.

[0294] 168. Use of any one of items 155 to 164, wherein the CDK4 / 6 inhibitor has the following structure:

[0295] Or its pharmaceutically acceptable salt.

[0296] 169. The use of any one of items 155 to 168, wherein the CDK4 / 6 inhibitor and the FGFR inhibitor are administered to the host at least once daily for at least 28 consecutive days.

[0297] 170. The use of any one of items 155 to 168, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 35 consecutive days.

[0298] 171. The use of any one of items 155 to 168, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the host at least once daily for at least 56 consecutive days.

[0299] 172. The use of any one of items 155 to 171, wherein the host has not received CDK4 / 6 inhibitor treatment at the time of the first administration of the CDK4 / 6 inhibitor.

[0300] 173. The use of any one of items 155 to 172, wherein, at the time of the first administration of the CDK4 / 6 inhibitor, the cancer has acquired resistance to one or more previously administered FGFR inhibitors.

[0301] 174. The use according to any one of items 155 to 173, wherein the cancer has acquired a mutation at the time of the first administration of the CDK4 / 6 inhibitor, making the cancer susceptible to developing resistance to one or more FGFR-TKIs. Summary of the Invention

[0302] This invention provides advantageous compositions and uses for administration to a host (e.g., a human) suffering from cancer with dysregulation of the FGFR signaling pathway caused by abnormalities of FGFR family members or FGF abnormalities, comprising an effective amount of the selective CDK4 / 6 inhibitor described herein, in combination with or alternating with an effective amount of a fibroblast growth factor receptor (FGFR) inhibitor (e.g., a selective FGFR-tyrosine kinase inhibitor (TKI)). The combined or alternating administration of the selective FGFR inhibitor with the selective CDK4 / 6 inhibitor provides a significant advantage against tumor growth and progression, and in some cases, synergistic inhibition, which increases therapeutic efficacy and may reduce or delay the acquisition of acquired resistance (see, e.g., Figure 1A , 1B And 1C, and Figure 2 (and the examples below). By incorporating the selective CDK4 / 6 inhibitors described herein into treatment regimens that include FGFR inhibitors (e.g., selective FGFR-TKIs), the chosen combination provides effective anticancer therapy that can prolong cancer proliferation inhibition, with limited administration of the additive toxicities caused by CDK4 / 6 inhibitors.

[0303] It is well known that while FGFR inhibitors (such as FGFR-TKIs) are beneficial treatments for suitable cancer patients with FGFR abnormalities, their long-term use is associated with the potential development of acquired resistance to their inhibitory effects in the cancer being treated. Furthermore, the use of FGFR-TKIs is associated with a high incidence of side effects that can be difficult to manage. For example, common adverse events associated with non-selective FGFR-TKIs include fatigue, anorexia, fever, gastrointestinal symptoms, arthralgia, hepatotoxicity, hypertension, proteinuria, thrombotic microangiopathy, and hyperthyroidism. Common adverse events associated with selective FGFR-TKIs include hyperphosphatemia, alopecia, dry mucous membranes, taste disturbances, mucositis, dry eye, onycholysis, diarrhea, conjunctivitis, keratitis, osteoarthritis, myalgia, and muscle spasms. The high incidence of side effects makes the combination of other anticancer agents with FGFR inhibitors challenging. The compositions and uses of the present invention provide synergistic inhibition while combating the development of FGFR inhibitor resistance by using the highly selective, transient CDK4 / 6 inhibitors described herein without significantly increasing the side effects associated with FGFR inhibitor use.

[0304] In some embodiments, the CDK4 / 6 inhibitors described herein can be administered in combination with FGFR inhibitors in a manner that allows for daily administration of both the CDK4 / 6 inhibitor and the FGFR inhibitor to the host. This daily administration of either the CDK4 / 6 inhibitor or the CDK4 / 6 inhibitor and the FGFR inhibitor does not result in a drug holiday or serious side effect accumulation issues, such as severe dose-limiting gastrointestinal problems or neutropenia, as seen with other CDK4 / 6 inhibitors (such as palbociclib), which is approved for the treatment of ER+, HER2- metastatic breast cancer but requires a drug holiday due to its associated myelosuppressive side effects. The combination of the CDK4 / 6 inhibitor and the FGFR inhibitor described herein for the compositions and uses described herein is short-acting, with a short half-life (less than about 18 hours) and limited side effects, thus allowing its inclusion in long-term treatment regimens without the need for a treatment holiday due to the use of the CDK4 / 6 inhibitor. Furthermore, by using these specific CDK4 / 6 inhibitors, the treatment-limiting side effects associated with other CDK4 / 6 inhibitors, such as neutropenia and gastrointestinal complications, are avoided, and the potential stacking of treatment-limiting side effects associated with the combination of CDK4 / 6 inhibitors and FGFR inhibitors can be significantly reduced in combination therapy. The CDK4 / 6 inhibitors described herein are particularly suitable for treatment regimens requiring long-term therapy, such as those in gastric adenocarcinoma, non-small cell lung cancer, breast cancer, and hepatocellular carcinoma and intrahepatic cholangiocarcinoma requiring FGFR inhibitor therapy, while minimizing the effects of CDK4 / 6 inhibitory toxicity on CDK4 / 6 replication-dependent healthy cells, such as hematopoietic stem cells and hematopoietic progenitor cells (collectively referred to as HSPCs).

[0305] Because of the reduced risk of side effects associated with treating abnormal cell proliferation (such as cancers with dysregulated fibroblast growth factor receptor (FGFR) signaling) with the CDK4 / 6 inhibitors described herein, prolonged continuous daily dosing of the CDK4 / 6 inhibitor, or a combination of the CDK4 / 6 inhibitor and the FGFR inhibitor, is possible, for example, 14 days or longer, 21 days or longer, 24 days or longer, 28 days or longer, 35 days or longer, 42 days or longer, 84 days or longer, 168 days or longer. In alternative embodiments, the FGFR inhibitor is administered at a set schedule, such as once every three weeks, once weekly, daily for 5 days in a 7-day cycle, daily for 14 days in a 21-day cycle, or daily for 21 days in a 28-day cycle, or daily for 28 days in a 28-day cycle, and the CDK4 / 6 inhibitor is administered daily throughout the cycle. In some embodiments, the CDK4 / 6 inhibitor is administered twice daily. In other alternative implementations, the administration period of the FGFR inhibitor is extended to continuous daily administration, for example, for 14 days or longer, 21 days or longer, 24 days or longer, 28 days or longer, 35 days or longer, 42 days or longer, 84 days or longer, 168 days or longer, and the CDK4 / 6 inhibitors described herein are administered intermittently, for example, at least once a week, at least once every ten days, at least once every two weeks, at least once every three weeks, or at least once a month. In yet another alternative implementation, the CDK4 / 6 inhibitors described herein are administered at least according to the same administration schedule as the FGFR inhibitors.

[0306] The CDK4 / 6 inhibitors used in the compositions and treatments described herein are selective, short-acting CDK4 / 6 inhibitors selected from:

[0307]

[0308]

[0309] Where R is C(H)X, NX, C(H)Y, or C(X)2.

[0310] Wherein X is hydrogen, a straight-chain, branched, or cyclic C1 to C5 alkyl group, including methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, cyclobutyl, pentyl, isopentyl, neopentyl, tert-pentyl, sec-pentyl, and cyclopentyl; and

[0311] Y is NR1R2, where R1 and R2 are independently X, or where R1 and R2 are alkyl groups that together form a bridge containing one or two heteroatoms (N, O, or S).

[0312] Furthermore, both X groups can form alkyl bridges or bridges containing one or two heteroatoms (N, O, or S) to form spirocyclic compounds, or

[0313]

[0314] Where R is NX and where X is hydrogen, isopropyl or methyl;

[0315] Or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition. Compounds I-VI are described, for example, in US 2013 / 0237544, which is incorporated herein by reference.

[0316] Compound I, also known as "lerociclib", was developed by G1 Therapeutics, Inc. and has been studied in multiple human clinical trials as an anti-tumor drug in combination with the EGFR inhibitor osimertinib. 1) Combined use for the treatment of EGFR-mutant non-small cell lung cancer, and 2) Combined use with fulvestrant for the treatment of ER+, HER2- breast cancer.

[0317] Compound III, also known as "trilacidine," developed by G1 Therapeutics, Inc., is currently being investigated in multiple human clinical trials as a myeloprotectant administered intravenously prior to chemotherapy for: 1) gemcitabine and carboplatin in metastatic triple-negative breast cancer (mTNBC), 2) topotecan in advanced small cell lung cancer (SCLC), 3) carboplatin and etoposide in SCLC, and 4) carboplatin, etoposide, and the PD-L1 immune checkpoint inhibitor atezolizumab in SCLC.

[0318] Cancers with dysregulated FGFR signaling pathways that can be treated with the compositions and treatments described herein include, but are not limited to, liver cancer, including hepatocellular carcinoma and intrahepatic bile duct carcinoma; gastric and esophageal cancer; endometrial cancer; ovarian cancer; gastric cancer, including gastric adenocarcinoma; glioma, including glioblastoma; head and neck cancer; breast cancer, including ER+ / HER2+ breast cancer; non-small cell lung cancer (NSCLC), including squamous cell lung cancer and large cell lung cancer; pilocytic astrocytoma and rhabdomyosarcoma; and other cancers described herein that may be sensitive to FGFR inhibition due to FGFR or FGF abnormalities. Cancers that can be treated with the compositions and treatments described herein include those with dysregulated FGFR signaling pathways that lead to abnormal proliferation, which may occur through, but are not limited to, FGFR gene amplification, FGFR overexpression, FGFR translocation fusion, FGFR point mutation and FGFR gene rearrangement, or other alterations in FGFR activating molecules, or FGF abnormalities, such as FGF overexpression or amplification. In some embodiments, the cancer is not urothelial carcinoma. In some implementations, the cancer is advanced or metastatic.

[0319] In one aspect, the FGFR inhibitor used in combination with or alternated with the CDK4 / 6 inhibitors described herein is a selective FGFR inhibitor, such as a selective FGFR-tyrosine kinase inhibitor (TKI). In an alternative embodiment, the FGFR inhibitor used for administration may be selected from non-selective FGFR inhibitors, selective FGFR monoclonal antibodies, and FGF traps.

[0320] In a specific instance, the CDK4 / 6 inhibitors described herein are administered in combination with selective FGFR inhibitors to hosts with cancers exhibiting aberrant FGFR signaling pathways. Selective FGFR inhibitors typically preferentially inhibit FGFR signaling activity rather than other targets, although inhibition of other targets may occur to a lesser extent. Selective FGFR inhibitors used in the methods described herein include, but are not limited to, erdatinib (Janssen, BALVERSA), infliximab (BGJ398, QED Therapeutics), pemitinib (PEMAZYRE; INCB54828, Incyte), AZD4547 (AstraZeneca), fabatinib (TAS-120; Taiho Pharmaceuticals), derlatinib (Arqule, ARQ087), robrutinib (FGF-401, Novartis), LY287445 (Eli Lilly), INCB062079 (Incyte), BLU9931 (Blueprint Medicines), and PRN1371 (Principia). Biopharma, PD173074 (Pfizer), Debio1347 (Debiopharm), fexotinib, H3B-6527, bemarituzumab, alonib, MGFR1877S, vorvastatinib, and FIIN-2. In some embodiments, CDK4 / 6 inhibitors selected from compounds I-VI are combined with or alternately administered with erdatinib. In some embodiments, CDK4 / 6 inhibitors selected from compounds I-VI are combined with or alternately administered with inflavrazinib. In some embodiments, CDK4 / 6 inhibitors selected from compounds I-VI are combined with or alternately administered with pemitinib. In some embodiments, CDK4 / 6 inhibitors selected from compounds I-VI are combined with or alternately administered with AZD4547. In some embodiments, CDK4 / 6 inhibitors selected from compounds I-VI are combined with or alternately administered with fabatinib (TAS-120). In some embodiments, CDK4 / 6 inhibitors selected from compounds I-VI are combined with or alternately administered with derazatanib. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternates with roburotinib. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternates with LY287445. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternates with INCB062079. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternates with BLU9931.In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternately with PRN1371. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternately with PD1733074. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternately with Debio1347. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternately with FIIN-2. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternately with H3B-6527. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternately with fexotinib. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternately with alonib. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternately with MGFR1877S. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternates with vorvastatin. A CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternates with inflavrazinib. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternates with bemarituzumab. In some embodiments, the selective CDK4 / 6 inhibitor administered is compound VI. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, the cancer is non-small cell lung cancer with FGFR abnormalities. In some embodiments, the non-small cell lung cancer is squamous cell lung cancer. In some embodiments, the non-small cell lung cancer is large cell lung cancer. In some embodiments, the cancer is gastric adenocarcinoma with FGFR abnormalities.

[0321] In one aspect, the present invention provides compositions and methods for treating patients with cancer exhibiting dysregulation of the FGFR signaling pathway due to abnormalities in members of the FGFR family, wherein the treatment comprises administering to the patient an effective amount of a combination of the selective CDK4 / 6 inhibitor described herein and an effective amount of an FGFR inhibitor (such as a selective FGFR-TKI), wherein the administration of the CDK4 / 6 inhibitor enhances anticancer activity and / or delays the development of cancer resistance to the FGFR inhibitor. In particular, the combination of the selective CDK4 / 6 inhibitor described herein with the FGFR inhibitor can effectively delay the initiation of acquired resistance or reduce acquired resistance to the administered FGFR inhibitor. Therefore, the compositions and their use in the treatments described herein can prolong the duration of an effective response to FGFR inhibitor therapy in cancer.

[0322] In one aspect of the invention, compositions and methods are provided for treating patients with cancer exhibiting FGFR signaling dysregulation, wherein the treatment comprises administering a therapeutically effective amount of the selective CDK4 / 6 inhibitor described herein combined with an effective amount of an FGFR inhibitor, wherein the patient has not previously received treatment with FGFR inhibitors and CDK4 / 6 inhibitors. In some embodiments, the administered selective CDK4 / 6 inhibitor is compound VI. In some embodiments, the selective CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B. In some embodiments, the selective CDK4 / 6 inhibitor is compound III. In some embodiments, the FGFR inhibitor is a selective FGFR inhibitor. In some embodiments, the selective CDK4 / 6 inhibitor is selected from erdatinib, inflavinib, pemitinib, AZD4547, fobatinib, deratinib, robrutinib, LY287445, INCB062079, PD173074, FIIN-2, fexotinib, H3B-6527, alonib, MGFR1877S, vorvastatinib, bemarituzumab, or Debio1347. In some embodiments, the FGFR inhibitor is erdatinib. In some embodiments, the FGFR inhibitor is inflavinib. In some embodiments, the FGFR inhibitor is pemitinib. In some embodiments, the FGFR inhibitor is AZD4547. In some embodiments, the FGFR inhibitor is fobatinib. In some embodiments, the FGFR inhibitor is deratinib. In some embodiments, the FGFR inhibitor is roblatinib. In some embodiments, the FGFR inhibitor is LY287445. In some embodiments, the FGFR inhibitor is INCB062079. In some embodiments, the FGFR inhibitor is Debio1347. In some embodiments, the FGFR inhibitor is FIIN-2. In some embodiments, the FGFR inhibitor is fexotinib. In some embodiments, the FGFR inhibitor is H3B-6527. In some embodiments, the FGFR inhibitor is BLU9931. In some embodiments, the FGFR inhibitor is PRN1371. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is combined with or alternates with alonib. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is combined with or alternates with MGFR1877S. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is combined with or alternates with vorvastatin. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is combined with or alternates with bemarituzumab. In some embodiments, the cancer is non-small cell lung cancer with FGFR abnormalities.In some embodiments, the non-small cell lung cancer is squamous cell lung cancer. In some embodiments, the non-small cell lung cancer is large cell lung cancer. In some embodiments, the cancer is gastric adenocarcinoma with FGFR abnormalities.

[0323] In one aspect of the invention, compositions and methods of treatment are provided for treating patients with cancer exhibiting FGFR signaling dysregulation, wherein the treatment comprises administering a therapeutically effective amount of the selective CDK4 / 6 inhibitor described herein combined with an effective amount of an FGFR inhibitor, wherein the patient has not previously received CDK4 / 6 inhibitor treatment. In some embodiments, the administered selective CDK4 / 6 inhibitor is compound VI. In some embodiments, the selective CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B. In alternative embodiments, the selective CDK4 / 6 inhibitor is compound III. In some embodiments, the FGFR-TKI is selected from erdatinib, inflavinib, pemitinib, AZD4547, fobatinib (TAS-120), deratinib, robrutinib, LY287445, INCB062079, FIIN-2, fexotinib, H3B-6527, alonib, MGFR1877S, vorvastatinib, bemarituzumab, or Debio1347. In some embodiments, the FGFR inhibitor is erdatinib. In some embodiments, the FGFR inhibitor is inflavinib. In some embodiments, the FGFR inhibitor is pemitinib. In some embodiments, the FGFR inhibitor is AZD4547. In some embodiments, the FGFR inhibitor is fobatinib. In some embodiments, the FGFR inhibitor is deratinib. In some embodiments, the FGFR inhibitor is roblatinib. In some embodiments, the FGFR inhibitor is LY287445. In some embodiments, the FGFR inhibitor is INCB062079. In some embodiments, the FGFR inhibitor is Debio1347. In some embodiments, the FGFR inhibitor is FIIN-2. In some embodiments, the FGFR inhibitor is fexotinib. In some embodiments, the FGFR inhibitor is H3B-6527. In some embodiments, the FGFR inhibitor is BLU9931. In some embodiments, the FGFR inhibitor is PRN1371. In some embodiments, the FGFR inhibitor is PD173074. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is combined with or alternates with alonib. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is combined with or alternates with MGFR1877S. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is combined with or alternates with vorvastatin. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is combined with or alternates with bemarituzumab. In some implementations, the cancer is non-small cell lung cancer with an abnormal FGFR.In some embodiments, the non-small cell lung cancer is squamous cell lung cancer. In some embodiments, the non-small cell lung cancer is large cell lung cancer. In some embodiments, the cancer is gastric adenocarcinoma with FGFR abnormalities.

[0324] In an alternative aspect, this document provides compositions and treatments for treating a host suffering from cancer with a dysregulated FGFR signaling pathway, wherein said treatment comprises:

[0325] a) Confirmation of FGFR abnormalities in cancer;

[0326] b) Administer an effective dose of a selective FGFR inhibitor to the patient; and,

[0327] c) Administer to the patient an effective amount of the combination of the selective CDK4 / 6 inhibitor and the FGFR inhibitor described herein. In some embodiments, the selective CDK4 / 6 inhibitor administered is compound VI. In some embodiments, the selective CDK4 / 6 inhibitor administered is compound I, compound IA, or compound IA, type B. In alternative embodiments, the selective CDK4 / 6 inhibitor administered is compound III. In some embodiments, the FGFR inhibitor is a selective FGFR inhibitor. In some embodiments, the FGFR-TKI is selected from erdatinib, inflavrazinib, pemitinib, AZD4547, fabatinib (TAS-120), deratinib, robrutinib, LY287445, INCB062079, FIIN-2, fexotinib, H3B-6527, alonib, MGFR1877S, vorvastatinab, bemarituzumab, or Debio1347. In some embodiments, the FGFR inhibitor is erdatinib. In some embodiments, the FGFR inhibitor is infuratinib. In some embodiments, the FGFR inhibitor is pemitinib. In some embodiments, the FGFR inhibitor is AZD4547. In some embodiments, the FGFR inhibitor is fabatinib. In some embodiments, the FGFR inhibitor is deratinib. In some embodiments, the FGFR inhibitor is roblatinib. In some embodiments, the FGFR inhibitor is LY287445. In some embodiments, the FGFR inhibitor is INCB062079. In some embodiments, the FGFR inhibitor is Debio1347. In some embodiments, the FGFR inhibitor is FIIN-2. In some embodiments, the FGFR inhibitor is fexotinib. In some embodiments, the FGFR inhibitor is H3B-6527. In some embodiments, the FGFR inhibitor is BLU9931. In some embodiments, the FGFR inhibitor is PRN1371. In some embodiments, the FGFR inhibitor is PD173074. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternately with aronibub. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternately with MGFR1877S. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternately with vorvastatin. In some embodiments, the FGFR inhibitor is AZD4547. In some embodiments, the FGFR inhibitor is bemarituzumab. In some embodiments, the cancer is non-small cell lung cancer with FGFR abnormalities. In some embodiments, the non-small cell lung cancer is squamous cell lung cancer. In some embodiments, the non-small cell lung cancer is large cell lung cancer.

[0328] In an alternative aspect, this document provides compositions and treatments for treating a host suffering from cancer with a dysregulated FGFR signaling pathway, wherein said treatment comprises:

[0329] a) Administer FGFR inhibitors to the patient;

[0330] b) Monitor patients for FGFR abnormalities; and,

[0331] c) When an FGFR abnormality or mutation, or a non-FGFR mutation, conferring resistance to FGFR inhibitors in cancer is detected, the patient is administered a combination of the selective CDK4 / 6 inhibitor described herein and an FGFR inhibitor. In some embodiments, the FGFR abnormality is an FGFR1 V561M substitution, an FGFR2 V565I mutation, an FGFR2 N550K mutation, an FGFR2 V564 mutation, or an FGFR3 V555M mutation. In some embodiments, the selective CDK4 / 6 inhibitor administered is compound I, compound IA, or compound IA, type B. In some embodiments, the selective CDK4 / 6 inhibitor administered is compound III. In some embodiments, the FGFR inhibitor is infuratinib. In some embodiments, the FGFR inhibitor is pemitinib. In some embodiments, the FGFR inhibitor is AZD4547. In some embodiments, the FGFR inhibitor is fabatinib. In some embodiments, the FGFR inhibitor is deratinib. In some embodiments, the FGFR inhibitor is roblatinib. In some embodiments, the FGFR inhibitor is LY287445. In some embodiments, the FGFR inhibitor is INCB062079. In some embodiments, the FGFR inhibitor is alonib. In some embodiments, the FGFR inhibitor is bemarituzumab. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is combined with or alternates with MGFR1877S. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is combined with or alternates with vorvastatin. In some embodiments, the FGFR inhibitor is Debio1347. In some embodiments, the FGFR inhibitor is FIIN-2. In some embodiments, the FGFR inhibitor is fexotinib. In some embodiments, the FGFR inhibitor is H3B-6527. In some embodiments, the FGFR inhibitor is BLU9931. In some embodiments, the FGFR inhibitor is PRN1371. In some embodiments, the FGFR inhibitor is PD173074. In some embodiments, the cancer is non-small cell lung cancer with an abnormal FGFR. In some embodiments, the non-small cell lung cancer is squamous cell lung cancer. In some embodiments, the non-small cell lung cancer is large cell lung cancer. In some embodiments, the cancer is gastric adenocarcinoma with an abnormal FGFR.

[0332] The administration regimens used in this invention may include daily administration of both an FGFR inhibitor and a CDK 4 / 6 inhibitor. For example, the FGFR inhibitor may be administered at least once daily along with the CDK 4 / 6 inhibitor. Alternatively, the FGFR inhibitor may be administered at least once daily and the CDK 4 / 6 inhibitor may be administered at least once daily, such as once daily, twice daily, or three times daily. Because the CDK 4 / 6 inhibitors described herein are highly tolerable, the treatment regimens can be administered continuously for extended periods without drug holidays, further prolonging the beneficial effects of the combination. Therefore, this invention provides compositions and treatment methods for treating cancers with FGFR or FGF abnormalities, wherein said treatment comprises administering a combination of the CDK 4 / 6 inhibitor and the FGFR inhibitor described herein, wherein said combination is administered continuously, for example, for at least 14 days, at least 21 days, at least 28 days, at least 35 days, at least 56 days, at least 70 days, at least 102 days, at least 204 days, or longer, without predetermined drug holidays. In some embodiments, the oral dosing regimen comprises about 200 mg, 300 mg, 400 mg, 500 mg, or 650 mg of a CDK 4 / 6 inhibitor, administered once daily. In some embodiments, the oral dosing regimen comprises about 100 mg, 150 mg, or 200 mg of a CDK 4 / 6 inhibitor, administered twice daily, optionally with an interval of about 12 hours. In some embodiments, the CDK 4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, and is administered orally at a dose of 150 mg twice daily. In some embodiments, the CDK 4 / 6 inhibitor is compound III.

[0333] In an alternative implementation, the standard dosing regimen for FGFR inhibitors is to administer them daily with predetermined drug holidays, such as the first 5 days of a 7-day cycle, the first 14 days of a 21-day cycle, or the first 21 days of a 28-day cycle. CDK4 / 6 inhibitors may be administered daily during the FGFR administration cycle, and CDK4 / 6 inhibitors may continue to be administered daily throughout the cycle if FGFR is not administered during a period of time in the cycle (“off period” or “holiday”). Attached Figure Description

[0334] Figure 1A IC50 of H1581(FGFR1m) NSCLC cells treated with mediator (DMSO), 300 nM Lerociclib, 300 nM erdatinib, 300 nM Lerociclib + 300 nM erdatinib, and 300 nM palbociclib + 300 nM erdatinib 50 The curve is a line graph. The x-axis is log[inhibitor], and the y-axis is the relative absorbance compared to the DMSO control.

[0335] Figure 1B IC50 of Snu-16 (FGFR2m) gastric cancer cells treated with mediator (DMSO), 300 nM Lerociclib, 300 nM erdatinib, 300 nM Lerociclib + 300 nM erdatinib, and 300 nM palbociclib + 300 nM erdatinib 50 The curve is a line graph. The x-axis is log[inhibitor], and the y-axis is the relative absorbance compared to the DMSO control.

[0336] Figure 1C IC50 of RT4 (FGFR3m) bladder cancer cells treated with mediator (DMSO), 300 nM Lerociclib, 300 nM erdatinib, 300 nM Lerociclib + 300 nM erdatinib, and 300 nM palbociclib + 300 nM erdatinib 50 The curve is a line graph. The x-axis is log[inhibitor], and the y-axis is the relative absorbance compared to the DMSO control.

[0337] Figure 2 This is a line graph showing the absorbance of dissolved crystal violet dye after 7, 13, 18, and 25 days of treatment with the medium (DMSO), 300 nM Lerociclib, 100 nM erdatinib, or 100 nM Lerociclib + 300 nM erdatinib on RT4 (FGFR3m) bladder cancer cells. The x-axis represents time measured in days. The y-axis represents absorbance measured at 562 nm. Detailed Implementation

[0338] Definitions

[0339] Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0340] The term "a / an" does not indicate a limitation of quantity, but rather the presence of at least one of the mentioned items. The term "or" means "and / or". Unless otherwise indicated herein, the description of ranges of values ​​is intended only as a shorthand method for individually referring to each individual value falling within the range, and each individual value is incorporated into this specification as if it were described individually herein. The endpoints of all ranges are included within the range and can be combined independently. Unless otherwise indicated herein or clearly contradicted by the context, all methods described herein may be performed in a suitable order. Unless otherwise stated, the use of examples or exemplary language (e.g., "such as") is intended only to better illustrate the invention and does not constitute a limitation on the scope of the invention. Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0341] As used in this article, "effective amount" refers to the amount that provides therapeutic or preventative benefits.

[0342] As used herein, the term “treatment” for a disease refers to reducing the frequency or severity of at least one sign or symptom of a disease or condition experienced by a patient (i.e., palliative treatment) or reducing the cause or effect of the disease or condition (i.e., disease-improving treatment).

[0343] Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the use of a range format is for convenience only and should not be construed as limiting the scope of the invention. A range description should be considered as a specific disclosure of all possible subranges and the individual values ​​within those ranges. For example, a range such as 1 to 6 should be considered as a specific disclosure of subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and the individual numbers within those ranges, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0344] "Dosage form" refers to the unit of administration of the active ingredient. Non-restrictive dosage forms include tablets, capsules, injections, suspensions, liquids, intravenous infusions, emulsions, creams, ointments, suppositories, inhalable dosage forms, and transdermal dosage forms. In some embodiments, the dosage form is a solid tablet or capsule.

[0345] "Parenteral" administration of the compound includes, for example, subcutaneous (sc), intravenous (iv), intramuscular (im), or intrasternal injection or infusion techniques.

[0346] As used herein, a “pharmaceutical composition” is a composition comprising at least one active agent (a compound or salt of one of the active compounds disclosed herein) and at least one other substance such as a carrier. A “pharmaceutical combination” is a combination of at least two active agents that may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents will be used together to treat any of the conditions described herein.

[0347] As used herein, a "pharmaceutically acceptable salt" is a derivative of the disclosed compound, wherein the parent compound is modified by preparing its inorganic and organic, non-toxic, acidic or basic addition salt. Salts of the compounds of the present invention can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Typically, such salts are prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water, in an organic solvent, or in a mixture of both. Typically, where feasible, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. Salts of the compounds of the present invention also include the compound and a solvate of the compound salt.

[0348] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and so on. Pharmaceutically acceptable salts include conventional non-toxic salts and quaternary ammonium salts of parent compounds formed from, for example, non-toxic inorganic or organic acids. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pyric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethanesulfonic acid, HOOC-(CH2)n-COOH (where n is 0-4), etc., or using different acids that will produce the same counterion. A list of other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., p. 1418 (1985). In determining the administration of a particular compound using the methods described herein, it should be understood that, where applicable, administration of a pharmaceutically acceptable salt of the compound is included as an implementation method.

[0349] As used herein, the term "prodrug" refers to a compound that, when administered to a host in vivo, is converted into a parent drug. As used herein, the term "parent drug" refers to any compound currently described that can be used to treat any of the conditions described herein, or to control or improve the underlying cause or symptoms associated with any physiological or pathological disorder in the host (typically a human) described herein. Prodrugs can be used to achieve any desired effect, including enhancing the properties of the parent drug or improving its pharmaceutical or pharmacokinetic properties. Existing prodrug strategies provide options in regulating the conditions for the production of the parent drug in vivo, all of which are considered to be included herein. Non-limiting examples of prodrug strategies include covalent attachment of a removable group or a removable portion of a group, such as, but not limited to, acylation, phosphorylation, phosphonylation, aminophosphate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxyl derivatives, sulfoxide or sulfone derivatives, carbonylation, or anhydrides, etc.

[0350] The term "carrier" used in pharmaceutical compositions / combinations of the present invention refers to a diluent, excipient, or medium provided together with the active compound.

[0351] The “patient” or “host” being treated is typically a human patient, but it should be understood that the methods described herein are effective for other animals, such as mammals. More specifically, the term patient can include animals used for assays, such as those used for preclinical testing, including, but not limited to, mice, rats, monkeys, dogs, pigs, and rabbits; as well as domesticated pigs (boars and castrated pigs), ruminants, horses, poultry, felines, bovines, rodents, canines, etc.

[0352] As used herein, “acquired resistance” refers to a condition in which cancers that were initially sensitive to or sensitive to the inhibitory effects of an inhibitory compound become unresponsive or less responsive over time. Without wishing to be bound by any single theory, it is believed that acquired resistance to an inhibitor occurs due to one or more other mutations or genetic alterations in bypass signaling pathways that develop after the initiation of inhibitor therapy. In some embodiments, a tumor or cancer exhibiting acquired resistance to an inhibitor is a cell population in which less than 50%, 40%, 30%, 20%, 15%, 10%, or 5% of its cells experience inhibition, leading to disease progression.

[0353] "Off-cycle" or "drug holiday" refers to a period of time during which the host is not administered or exposed to CDK4 / 6 inhibitors and / or FGFR inhibitors. For example, in a treatment regimen in which the host is administered CDK4 / 6 inhibitors and / or FGFR inhibitors for 21 consecutive days and not administered CDK4 / 6 inhibitors and / or FGFR inhibitors for 7 consecutive days, and this regimen is repeated multiple times or multiple cycles, the 7-day non-administration period is considered an "off-cycle" or "drug holiday." Off-cycle and drug holiday can also refer to a treatment regimen interruption in which the host is not given CDK4 / 6 inhibitors and / or FGFR inhibitors for a period of time due to harmful side effects, such as bone marrow suppression, diarrhea, or other side effects that require discontinuation of administration.

[0354] CDK4 / 6 Inhibitors

[0355] The CDK4 / 6 inhibitors used in this invention include compound I, compound II, compound III, compound IV and compound V, or pharmaceutically acceptable salts thereof.

[0356] Publications describing such compounds include the following: WO 2014 / 144326, submitted by Strum et al. and assigned to G1 Therapeutics, describes compounds and methods for protecting normal cells during chemotherapy using pyrimidine-based CDK4 / 6 inhibitors. WO 2014 / 144596, submitted by Strum et al. and assigned to G1 Therapeutics, describes compounds and methods for protecting hematopoietic stem cells and progenitor cells from ionizing radiation using pyrimidine-based CDK4 / 6 inhibitors. WO 2014 / 144847, submitted by Strum et al. and assigned to G1 Therapeutics, describes HSPC preservation therapy for abnormal cell proliferation using pyrimidine-based CDK4 / 6 inhibitors. WO 2014 / 144740, submitted by Strum et al. and assigned to G1 Therapeutics, describes CDK4 / 6 inhibitors based on highly active antitumor and antiproliferative pyrimidines. WO 2015 / 161285, submitted by Strum et al. and assigned to G1 Therapeutics, describes a tricyclic pyrimidine-based CDK inhibitor for radiation protection. WO 2015 / 161287, submitted by Strum et al. and assigned to G1 Therapeutics, describes a similar tricyclic pyrimidine-based CDK inhibitor for protecting cells during chemotherapy. WO 2015 / 161283, submitted by Strum et al. and assigned to G1 Therapeutics, describes a similar tricyclic pyrimidine-based CDK inhibitor for the preservation therapy of HSPCs with RB-positive abnormal cell proliferation. WO 2015 / 161288, submitted by Strum et al. and assigned to G1 Therapeutics, describes a similar tricyclic pyrimidine-based CDK inhibitor used as an antitumor and antiproliferative agent. WO 2016 / 040858, submitted by Strum et al. and assigned to G1 Therapeutics, describes the combination use of pyrimidine-based CDK4 / 6 inhibitors with other antitumor agents. WO 2016 / 040848, submitted by Strum et al. and assigned to G1 Therapeutics, describes compounds and methods for treating certain Rb-negative cancers using CDK4 / 6 inhibitors and topoisomerase inhibitors. WO 2019 / 136451, submitted by Beelen et al. and assigned to G1 Therapeutics, describes specific dosing regimens for treating cancer using compound I. WO 2019 / 199883, submitted by Strum et al. and assigned to G1 Therapeutics, describes specific combinations of compound I and certain tyrosine kinase inhibitors for treating cancers with specific oncogenic driver mutations.

[0357] In one aspect, this article provides a composition for treating a host with dysregulated FGFR cancer, wherein the composition is compound I and the treatment comprises administering to the host an effective amount of compound I, or a pharmaceutically acceptable salt thereof, and an effective amount of an FGFR inhibitor. Compound I, named lerociclib(2'-((5-(4-isopropylpiperazin-1-yl)piperidin-2-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-6'-one), is a highly selective CDK4 / 6 inhibitor having the following structure:

[0358]

[0359] Lerociclib can be administered orally or intravenously, as previously described in US2013-0237544, which is incorporated herein by reference. Lerociclib can also be prepared as previously described in US 2019-0135820, which is incorporated herein by reference. Lerociclib induces inhibition of cell proliferation in a variety of CDK4 / 6-dependent tumorigenic cell lines, including breast, melanoma, leukemia, and lymphoma cells, and inhibits RB phosphorylation in vitro and in vivo. An article published in a peer-reviewed journal highlighted other beneficial therapeutic properties of lerociclib, including tumor selectivity relative to plasma in mouse xenograft tumors (Bisi, et al., Preclinical development of G1T38: A novel, potent and selective inhibitor of cyclin dependent kinases 4 / 6 for use as an oral antine oplastic in patients with CDK 4 / 6 sensitive tumors, Oncotarget, March 15, 2017). See also U.S. Patent No. 9,527,857.

[0360] In some embodiments, compound I is administered in the form of a dihydrochloride salt:

[0361]

[0362] In some embodiments, Lerociclib is administered in the isolated B-form of its dihydrochloride salt (compound IA, type B), characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2θ values ​​selected from the following: 6.5 ± 0.2°, 9.5 ± 0.2°, 14.0 ± 0.2°, 14.4 ± 0.2°, 18.1 ± 0.2°, 19.9 ± 0.2°, and 22.4 ± 0.2°, as described in US2020-0123168, the entire contents of which are incorporated herein by reference, and see Examples 3-5 below. In some embodiments, compound I, or a pharmaceutically acceptable salt thereof, compound IA, or compound IA, type B, is administered as an oral solid dosage form, once daily, at a dose of about 100 mg to 650 mg, or alternatively about 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 650 mg. In some embodiments, compound I, or a pharmaceutically acceptable salt thereof, compound IA, or compound IA, type B, is administered orally at a dose between 100 mg and 250 mg twice daily, or alternatively about 100 mg, 150 mg, 200 mg, or 250 mg, optionally at intervals of about 12 hours. In one particular embodiment, compound I, or a pharmaceutically acceptable salt thereof, compound IA, or compound IA, type B, is administered orally at a dose of about 150 mg twice daily. In some embodiments, compound I, or a pharmaceutically acceptable salt thereof, compound IA, or compound IA, type B, is administered orally at a dose of about 150 mg twice daily in a solid dosage form, including but not limited to solid tablets or capsules.

[0363] In other alternative implementations, the structure will be:

[0364] Compound II is a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof, administered as a composition for use as described herein. Compound II can be administered orally or intravenously. Compound II can be prepared as previously described in US 2014-0271466, which is incorporated herein by reference.

[0365] Compound III, named triasilib (2'-((5-(4-methylpiperazin-1-yl)piperidin-2-yl)amino)-7',8'-dihydro-6'H-spiro(cyclohexane-1,9'-pyrazino(1',2':1,5)pyrrolo(2,3-d)pyrimidine)-6'-one), is a highly selective CDK4 / 6 inhibitor with the following structure:

[0366]

[0367] As provided herein, tricrascitabine or its pharmaceutically acceptable salts, compositions, isotope analogs, or prodrugs are compositions for the purposes described herein. Trirascitabine may be administered in a suitable carrier. Trirascitabine is described in US2013-0237544, the entire contents of which are incorporated herein by reference. Trirascitabine may be synthesized as described in US2019-0135820, the entire contents of which are incorporated herein by reference. Trirascitabine may be administered in any manner that achieves the intended outcome, including systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration. For injection, in some embodiments, tricrascitabine may be provided, for example, as a sterile, lyophilized, yellow cake in 300 mg / vial, providing 300 mg of tricrascitabine (equivalent to 349 mg of tricrascitabine dihydrochloride). For example, the product may be provided in a single-use 20 mL clear glass vial, preservative-free. Prior to administration, 300 mg / vial of triacyltrimethoprim for injection can be reconstituted with 19.5 mL of 0.9% sodium chloride injection or 5% glucose injection. The reconstituted solution has a triacyltrimethoprim concentration of 15 mg / mL and is usually subsequently diluted before intravenous or other route of administration. In some embodiments, compound III is administered once daily via parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration. In some embodiments, compound III is administered every other day, every three days, weekly, every 10 days, every 14 days, every 21 days, or every 28 days via parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration. In some embodiments, compound III is administered at approximately 180 mg / mL. 2 Up to 300mg / m 2 The dosage is between [specific dosage ranges]. In some embodiments, compound III is administered at approximately 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0368] In other alternative implementations, the structure will be:

[0369] The CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof, is administered as a composition for use as described herein. Compound IV can be administered orally or intravenously. Compound IV can be prepared as previously described in US 2014-0271466, which is incorporated herein by reference.

[0370] In other alternative embodiments, CDK4 / 6 inhibitors have the following structures

[0371]

[0372] Where R is C(H)X, NX, C(H)Y, or C(X)2.

[0373] Wherein X is hydrogen or a straight-chain, branched, or cyclic C1 to C5 alkyl group, including methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, cyclobutyl, pentyl, isopentyl, neopentyl, tert-pentyl, sec-pentyl, and cyclopentyl; and

[0374] Y is NR1R2, where R1 and R2 are independently X, or where R1 and R2 are alkyl groups that together form a bridge containing one or two heteroatoms (N, O, or S).

[0375] Furthermore, the two X groups may together form an alkyl bridge or a bridge containing one or two heteroatoms (N, O, or S) to form a spirocyclic compound, or a pharmaceutically acceptable salt thereof, which is a composition for use as described herein. Compound V can be administered orally or intravenously. Compound V can be prepared as previously described in US2014-0271466, which is incorporated herein by reference.

[0376] In other alternative embodiments, CDK4 / 6 inhibitors have the following structures

[0377]

[0378] Wherein R is N×, and where X is hydrogen, methyl or isopropyl, which is a composition for use as described herein.

[0379] In alternative embodiments, CDK4 / 6 inhibitors other than those specifically described above may be used in this invention. Non-limiting examples include palbociclib, abecilib, and ribociclib.

[0380] FGFR Inhibitors

[0381] This invention provides compositions and treatments for treating a host with cancer having dysregulated FGFR signaling, wherein the treatment comprises administering to the host, in combination or alternately, a selective CDK4 / 6 inhibitor and an FGFR inhibitor as described herein. The FGFR inhibitor used in this invention may be selected from non-selective FGFR inhibitors, selective FGFR inhibitors, FGFR monoclonal antibodies, and FGF traps. In a particular embodiment, the FGFR inhibitor used herein is a selective FGFR inhibitor.

[0382] Selective FGFR inhibitors used in the compositions for the treatments described herein include, but are not limited to, erdatinib, inflavinib, pemitinib, AZD4547, fabatinib (TAS-120), deratinib, robrutinib, LY287445, INCB062079, BLU9931, PRN1371, FIIN-2, PD173074, H3B-6527, fexotinib, alonibub, bemarituzumab, vorvastatinab, MGFR1877S, and Debio1347, or any pharmaceutically acceptable salt thereof. In some embodiments, the FGFR inhibitor is not erdatinib.

[0383] In alternative embodiments, non-selective FGFR inhibitors that may be used in the compositions used in the treatments described herein include, but are not limited to, dovirtinib (Oncology Venture A / S), deritinib (Clovis Oncology), and lenvatinib (Eisai Pharmaceuticals, LENVIMA). TM ), Regfini (Bayer, Stivalga) TM Panatinib (Ariad Pharmaceuticals, Inc.) TM ), Boehringer Ingelheim, OFEV TM SOMCL-085, Pazopanib (Novartis, VOTRIENT) TM (or orantinib (Taiho Pharmaceuticals), or any pharmaceutically acceptable salt thereof.)

[0384] In alternative embodiments, the FGFR monoclonal antibody used in the treatments described herein includes, but is not limited to, bemarituzumab (FPA144, Five Prime Therapeutics), MGFR1877S (Genentech), and vorvastatin (B-701, Rainier Therapeutics). In some embodiments, a CDK4 / 6 inhibitor selected from compound IV is administered in combination with or alternates with bemarituzumab. In some embodiments, a CDK4 / 6 inhibitor selected from compound IV is administered in combination with or alternates with MGFR1877S. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternates with vorvastatin. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B. In alternative embodiments, the CDK4 / 6 inhibitor is compound III.

[0385] In alternative embodiments, the FGF ligand trap is a composition used in the treatment described herein. In some embodiments, a CDK4 / 6 inhibitor selected from compounds I-VI is administered in combination with or alternately with GSK3052230. In a particular embodiment, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B. In alternative embodiments, the CDK4 / 6 inhibitor is compound III.

[0386] In some embodiments, the FGFR inhibitors used in this invention include, but are not limited to, the FGFR inhibitors described below, or pharmaceutically acceptable salts thereof:

[0387] Erdatinib (Janssen, Balversa) TM Erdatinib is a selective kinase inhibitor that binds to and inhibits the enzymatic activity of FGFR1, FGFR2, FGFR3, and FGFR4. Erdatinib has the following chemical structure:

[0388]

[0389] Erdatinib is approved for the treatment of metastatic urothelial carcinoma with FGFR3 or FGFR2 alterations that has progressed beyond conventional platinum-based therapy. The initial dose of erdatinib is 8 mg once daily, depending on serum phosphate levels and tolerability on days 14 to 21. If serum phosphate levels are <5.5 mg / dL and no ocular disease or grade 2 or higher adverse events occur, the dose is typically increased to 9 mg once daily. Therefore, in some embodiments, the CDK4 / 6 inhibitor described herein is administered daily in combination with erdatinib to treat cancers with dysregulated or abnormal FGFR signaling, wherein the CDK4 / 6 inhibitor and erdatinib are administered for at least 21, 24, 28, 35, 42, 56 days, or longer. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at a dose of about 100 mg-200 mg, for example, 150 mg, and erdatinib is administered once daily at a dose of about 8 mg or 9 mg. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at a dose of about 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0390] Dovirtinib (Oncology Venture A / S) strongly binds to fibroblast growth factor receptor 3 (FGFR3) and inhibits its phosphorylation, leading to inhibition of tumor cell proliferation and induction of tumor cell death. Dovirtinib has the following chemical structure:

[0391]

[0392] Deritinib (Clovis Oncology) is a protein kinase inhibitor that blocks VEGF receptors 1, 2, and 3, as well as fibroblast growth factor receptors 1 and 2, and platelet-derived growth factor receptors α and β. Deritinib has the following chemical structure:

[0393]

[0394] Therefore, in some embodiments, the CDK4 / 6 inhibitor described herein is administered daily in combination with deritinib to treat cancers with FDFR-dysregulated signal transduction or abnormalities, wherein the CDK4 / 6 inhibitor and deritinib are administered for at least 21, 24, 28, 35, 42, 56 days, or longer. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at about 100 mg to 200 mg, for example, 150 mg, and deritinib is administered once daily at about 5 mg to 10 mg. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at about 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0395] Lenvatinib (Eisai Pharmaceuticals, LENVIMA) TM Lenvatinib has been approved for the treatment of locally recurrent or metastatic, progressive, and unresponsive differentiated thyroid cancer, and in combination with everolimus for the treatment of advanced renal cell carcinoma following prior anti-angiogenic therapy. Lenvatinib has the following chemical structure:

[0396]

[0397] Lenvatinib is a kinase inhibitor that inhibits the kinase activity of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). In addition to inhibiting normal cellular function, lenvatinib also inhibits other kinases associated with pathogenic angiogenesis, tumor growth, and cancer progression, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-derived growth factor receptor α (PDGFRα); and KIT. Lenvatinib also exhibits antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling, while inhibiting FGF receptor substrate 2α (FRS2α) phosphorylation. Therefore, in some embodiments, the CDK4 / 6 inhibitor described herein is administered daily in combination with lenvatinib to treat cancers with dysregulated or abnormal FGFR signaling, wherein the CDK4 / 6 inhibitor and lenvatinib are administered for at least 21, 24, 28, 35, 42, 56 days, or longer. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at a dose of about 100 mg to 200 mg, for example, 150 mg, and lenvatinib is administered once daily at a dose of about 8 mg to 24 mg. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at a dose of about 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0398] Regfini (Bayer, Stivalga) TM Regorafenib is an oral multi-kinase inhibitor developed by Bayer that targets angiogenesis, matrix, and oncogenic receptor tyrosine kinases (RTKs). Regorafenib has the following chemical structure:

[0399]

[0400] Regorafenib is approved for the treatment of colorectal cancer, gastrointestinal stromal tumors, and hepatocellular carcinoma, and is administered orally at a dose of 160 mg once daily for the first 21 days of each 28-day cycle. In some embodiments, this document provides compositions and treatments for treating cancers with FGFR dysregulation or signal transduction abnormalities, wherein the treatment comprises administration of the CDK4 / 6 inhibitor described herein and regorafenib, wherein the CDK4 / 6 inhibitor and regorafenib are administered daily for day 21 of a 28-day cycle. In some embodiments, the CDK4 / 6 inhibitor described herein is administered daily for day 28 of a 28-day cycle, and regorafenib is administered daily for day 21 of a 28-day cycle. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at a dose of about 100 mg to 200 mg, for example, 150 mg, and regorafenib is administered once daily at a dose of about 150 mg to 180 mg, wherein the CDK4 / 6 inhibitor is administered daily for at least 21 days, at least 24 days, or 28 days in a 28-day cycle, and regorafenib is administered daily for day 21 of a 28-day cycle. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at a dose of about 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0401] Ponatinib (Ariad Pharmaceuticals, Inc.) TM ) is an oral medication developed by ARIAD Pharmaceuticals for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). It is a multi-target tyrosine kinase inhibitor with the following chemical structure:

[0402]

[0403] Therefore, in some embodiments, the CDK4 / 6 inhibitor described herein is administered daily in combination with ponatinib to treat cancers with FGFR-dysregulated signal transduction or abnormalities, wherein the CDK4 / 6 inhibitor and ponatinib are administered for at least 21, 24, 28, 35, 42, 56 days, or longer. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at a dose of about 100 mg to 200 mg, for example, 150 mg, and ponatinib is administered once daily at a dose of about 30 mg to 45 mg. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at a dose of about 240 mg / m². 2For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0404] Boehringer Ingelheim, OFEVT M Nintedanib, marketed under the brand names Ofev and Vargatef, is an oral medication used to treat idiopathic pulmonary fibrosis and, in combination with other drugs, to treat certain types of non-small cell lung cancer. Nintedanib has the following chemical structure:

[0405]

[0406] Therefore, in some embodiments, the CDK4 / 6 inhibitor described herein is administered daily in combination with nintedanib to treat cancers with FGFR-dysregulated signal transduction or abnormalities, wherein the CDK4 / 6 inhibitor and nintedanib are administered for at least 21, 24, 28, 35, 42, 56 days, or longer. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at a dose of about 100 mg to 200 mg, for example, 150 mg, and nintedanib is administered twice daily at a dose of about 100 mg to about 200 mg, for example, 150 mg, twice daily, with an interval of about 12 hours. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at a dose of about 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0407] Novartis (Votrient) TM Pazopanib is a highly potent and selective multi-target receptor tyrosine kinase inhibitor that blocks tumor growth and inhibits angiogenesis. It has been approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Pazopanib has the following chemical structure:

[0408]

[0409] Therefore, in some embodiments, the CDK4 / 6 inhibitor described herein is administered daily in combination with pazopanib to treat cancers with FGFR-dysregulated signal transduction or abnormalities, wherein the CDK4 / 6 inhibitor and pazopanib are administered for at least 21, 24, 28, 35, 42, 56 days, or longer. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at about 100 mg to 200 mg, for example, 150 mg, and pazopanib is administered once daily at a dose between about 200 mg and about 800 mg. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at about 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0410] Orantinib (Taiho Pharmaceuticals) is an orally bioavailable receptor tyrosine kinase inhibitor. Orantinib binds to and inhibits the autophosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), thereby inhibiting angiogenesis and cell proliferation. Orantinib also inhibits the phosphorylation of stem cell factor receptor tyrosine kinase c-kit, which is normally expressed in acute myeloid leukemia cells. Orantinib has the following chemical structure:

[0411]

[0412] Therefore, in some embodiments, the CDK4 / 6 inhibitor described herein is administered daily in combination with orantinib to treat cancers with FGFR-dysregulated signal transduction or abnormalities, wherein the CDK4 / 6 inhibitor and orantinib are administered for at least 21, 24, 28, 35, 42, 56 days, or longer. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at about 100 mg to 200 mg, for example, 150 mg, and orantinib is administered twice daily at about 150 mg to 250 mg, for example, 200 mg twice daily. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at about 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0413] Infigliolatinib (BGJ398, QED Therapeutics) is an orally bioavailable pan-inhibitor of human fibroblast growth factor receptor (FGFR) with potential anti-angiogenic and anti-tumor activities. Infigliolatinib selectively binds to and inhibits FGFR activity, thereby inhibiting tumor angiogenesis and tumor cell proliferation, and inducing tumor cell death. The chemical structure of Infigliolatinib is as follows:

[0414]

[0415] Infinigratinib is administered once daily for 21 days during a 28-day cycle. In clinical trials, Infinigratinib has been administered once daily at doses ranging from approximately 50 mg to 150 mg. In some embodiments, this document provides a method of treating cancers with FGFR-dysregulated signal transduction or abnormalities by administering the CDK4 / 6 inhibitor described herein and Infinigratinib, wherein the CDK4 / 6 inhibitor and Infinigratinib are administered for 21 days daily during a 28-day cycle. In some embodiments, the CDK4 / 6 inhibitor described herein is administered for 28 days daily during a 28-day cycle, and Infinigratinib is administered for 21 days daily during a 28-day cycle. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at a dose of about 100 mg to 200 mg, for example, 150 mg, and inflistatinib is administered once daily at a dose of about 50 mg to 150 mg, wherein the CDK4 / 6 inhibitor is administered daily for at least 21 days, at least 24 days, or 28 days in a 28-day cycle, and inflistatinib is administered daily for 21 days in a 28-day cycle. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at a dose of about 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0416] Pemitinib (Pemazyre; INCB54828, Incyte) is a selective FGFR inhibitor approved for the treatment of patients with cholangiocarcinoma. Its chemical structure is as follows:

[0417]

[0418] Pemitinib is approved for the treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with fibroblast growth factor receptor 2 (FGFR2) fusions or other rearrangements detected by an FDA-approved test. Pemitinib is approved for administration of 13.5 mg daily for 14 days in a 21-day cycle. In some embodiments, this document provides a method of treating cancers with FGFR-dysregulated signaling or abnormalities by administering the CDK4 / 6 inhibitor described herein and pemitinib, wherein the CDK4 / 6 inhibitor and pemitinib are administered daily for 14 days in a 21-day cycle. In some embodiments, the CDK4 / 6 inhibitor described herein is administered daily for 21 days in a 21-day cycle, and pemitinib is administered daily for 21 days in a 28-day cycle. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at a dose of about 100 mg to 200 mg, for example, 150 mg, and pemitinib is administered once daily at a dose of about 10 mg to 15 mg, for example, about 13.5 mg, wherein the CDK4 / 6 inhibitor is administered daily for at least 14 days, at least 17 days, or 21 days in a 21-day cycle, and inflistatinib is administered daily for 14 days in a 28-day cycle. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at a dose of about 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0419] AZD4547 (AstraZeneca) is an orally bioavailable inhibitor of fibroblast growth factor receptor (FGFR) with antitumor activity. The FGFR inhibitor AZD4547 binds to and inhibits FGFR, which may lead to inhibition of FGFR-related signaling pathways, thereby suppressing tumor cell proliferation and tumor cell death. AZD4547 has the following chemical structure:

[0420]

[0421] In some embodiments, this document provides a method for treating cancers with FGFR-dysregulated signal transduction or abnormalities by administering the CDK4 / 6 inhibitor described herein and AZD4547, wherein the CDK4 / 6 inhibitor and AZD4547 are administered daily on a continuous schedule, for example, at least 21 days, 28 days, 35 days, or longer. In some embodiments, the CDK4 / 6 inhibitor described herein is administered daily for 28 days in a 28-day cycle, and AZD4547 is administered daily for 21 days in a 28-day cycle. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at a dose of about 100 mg to 200 mg, for example, 150 mg, and AZD4547 is administered twice daily at a dose of about 60 mg to 100 mg, for example, about 80 mg, wherein the CDK4 / 6 inhibitor is administered for at least 21, at least 24, or 28 days in a 28-day cycle, and AZD4547 is administered for at least 21, at least 24, or 28 days in a 28-day cycle. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at a dose of about 240 mg / m³. 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0422] Fabatinib (TAS-120; Taiho Pharmaceuticals) is a highly selective, orally bioavailable inhibitor of fibroblast growth factor receptor (FGFR) with antitumor activity. TAS-120 has the following chemical structure:

[0423]

[0424] In some embodiments, this document provides compositions and treatment methods for treating cancers with FGFR-dysregulated signal transduction or abnormalities, wherein said treatment comprises administration of the CDK4 / 6 inhibitor described herein and fobatinib, wherein the CDK4 / 6 inhibitor and fobatinib are administered daily on a continuous schedule, for example, at least 21 days, 28 days, 35 days, or longer. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at a dose of about 100 mg to 200 mg, for example, 150 mg, and fobatinib is administered once daily at a dose of about 10 mg to 30 mg, for example, about 20 mg. In some embodiments, the cancer with FGFR-dysregulated signal transduction is FGF19 overexpression or amplification. In some embodiments, the cancer is FGFR19-positive hepatocellular carcinoma, such as hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC). In some embodiments, the cancer is FGF19-positive esophageal cancer, nasopharyngeal carcinoma, or ovarian cancer. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is used at approximately 240 mg / m³. 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0425] Arqule (ARQ087) is an orally bioavailable fibroblast growth factor receptor (FGFR) inhibitor with an IC50 value of 1.8 nM against FGFR2, 4.5 nM against FGFR1 and 3, and even lower potency against FGFR4 (IC50 = 34 nM). Arqule has the following chemical structure:

[0426]

[0427] In some embodiments, this document provides compositions and treatment methods for treating cancers with FGFR-dysregulated signal transduction or abnormalities, wherein said treatment comprises administration of the CDK4 / 6 inhibitor and deratinib described herein, wherein the CDK4 / 6 inhibitor and deratinib are administered daily on a continuous schedule, for example, at least 21 days, 28 days, 35 days, or longer. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at about 100 mg to 200 mg, for example, 150 mg, and deratinib is administered once daily at a dose between about 10 mg and 30 mg, for example, about 20 mg. In some embodiments, the cancer with FGFR-dysregulated signal transduction is FGF19 overexpression or amplification. In some embodiments, the cancer is FGFR19-positive hepatocellular carcinoma, such as hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC). In some embodiments, the cancer is FGF19-positive esophageal cancer, nasopharyngeal carcinoma, or ovarian cancer. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is used at approximately 240 mg / m³. 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0428] Robrutinib (FGF-401, Novartis) is a selective inhibitor of FGFR4 with an IC50 of 1.1 nM. It binds reversibly and covalently to the FGFR4 kinase domain, exhibiting at least 1,000-fold selectivity against a panel of 65 kinases in biochemical assays. Robrutinib has the following chemical structure:

[0429]

[0430] In some embodiments, this document provides compositions and treatments for treating cancers with FGFR-dysregulated signal transduction or abnormalities, wherein said treatment comprises administration of the CDK4 / 6 inhibitor and robrutinib described herein, wherein the CDK4 / 6 inhibitor and robrutinib are administered daily on a continuous schedule, such as for at least 21 days, 28 days, 35 days, or longer. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered at about 100 mg-200 mg twice daily, such as 150 mg twice daily. In some embodiments, the cancer with FGFR-dysregulated signal transduction is FGF19 overexpression or amplification. In some embodiments, the cancer is FGFR19-positive hepatocellular carcinoma, such as hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC). In some embodiments, the cancer is FGF19-positive esophageal cancer, nasopharyngeal carcinoma, or ovarian cancer. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at about 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0431] Debio1347 (Debiopharm), also known as CH5183284, is a selective and orally available FGFR inhibitor with IC50 values ​​of 9.3 nM, 7.6 nM, 22 nM, and 290 nM against FGFR1, FGFR2, FGFR3, and FGFR4, respectively. Debio1347 has the following chemical structure:

[0432]

[0433] In some embodiments, this document provides a method of treating cancers with FGFR-dysregulated signaling or abnormalities by administering the CDK4 / 6 inhibitor described herein and Debio1347, wherein the CDK4 / 6 inhibitor and Debio1347 are administered daily on a continuous schedule, for example, at least 21 days, 28 days, 35 days, or longer. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at a dose of about 100 mg to 200 mg, for example, 150 mg, and Debio1347 is administered once daily at a dose of about 10 mg to 210 mg, for example, about 80 mg twice daily. In some embodiments, the cancer with FGFR-dysregulated signaling is FGF19 overexpression or amplification. In some embodiments, the cancer is FGFR19-positive hepatocellular carcinoma, such as hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC). In some embodiments, the cancer is FGF19-positive esophageal cancer, nasopharyngeal carcinoma, or ovarian cancer. In an alternative embodiment, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at approximately 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0434] BLU9931 (Blueprint Medicines) is a selective inhibitor of FGFR4 with an IC50 of 3.0 nM. It binds irreversibly to the FGFR kinase domain via covalent bonding. BLU9931 binds within the ATP-binding pocket of FGFR4 and forms a covalent bond with Cys552. The chemical structure of BLU9931 is as follows:

[0435]

[0436] In some embodiments, this document provides compositions and treatment methods for treating cancers with FGFR dysregulation or signal transduction abnormalities, wherein said treatment comprises administering the CDK4 / 6 inhibitor and BLU9931 described herein, wherein the CDK4 / 6 inhibitor and BLU9931 are administered daily on a continuous schedule, for example, at least 14 days, at least 21 days, at least 28 days, at least 35 days, or longer. In some embodiments, the CDK4 / 6 inhibitor described herein is administered daily for 28 days in a 28-day cycle, and BLU9931 is administered daily for 21 days in a 28-day cycle. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at a dose of about 100 mg to 200 mg, for example, 150 mg, or BLU9931 administered between about 10 mg and 250 mg, wherein the CDK4 / 6 inhibitor is administered for at least 21, 24, or 28 days daily in a 28-day cycle, and BLU9931 is administered for at least 21, 24, or 28 days daily in a 28-day cycle. In some embodiments, the cancer with FGFR-dysregulated signal transduction is FGF19 overexpression or amplification. In some embodiments, the cancer is FGFR19-positive hepatocellular carcinoma, such as hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC). In some embodiments, the cancer is FGF19-positive esophageal cancer, nasopharyngeal carcinoma, or ovarian cancer. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at a dose of about 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0437] PRN1371 (Principia Biopharma) is a highly selective and potent inhibitor of FGFR1-4 and CSF1R, with IC50 values ​​of 0.6, 1.3, 4.1, 19.3, and 8.1 nM for FGFR1, FGFR2, FGFR3, FGFR4, and CSF1R, respectively. PRN1371 targets cysteine ​​residues within the kinase domain. The chemical structure of PRN1371 is as follows:

[0438]

[0439] In some embodiments, this document provides compositions and treatments for treating cancers with FGFR-dysregulated signal transduction or abnormalities, wherein said treatment comprises administering the CDK4 / 6 inhibitor and PRN1371 described herein, wherein the CDK4 / 6 inhibitor and PRN1371 are administered daily on a continuous schedule, for example, at least 14 days, at least 21 days, at least 28 days, at least 35 days, or longer. In some embodiments, the CDK4 / 6 inhibitor described herein is administered for 21 days daily in a 28-day cycle, and PRN1371 is administered for 28 days daily in a 28-day cycle. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at a dose of about 100 mg to 200 mg, for example, 150 mg, and PRN1371 is administered between about 10 mg and 500 mg, wherein the CDK4 / 6 inhibitor is administered daily for at least 21, at least 24, or 28 days in a 28-day cycle, and PRN1371 is administered daily for at least 21, at least 24, or 28 days in a 28-day cycle. In some embodiments, the cancer with FGFR-dysregulated signal transduction is FGF19 overexpression or amplification. In some embodiments, the cancer is FGF19-positive hepatocellular carcinoma (HCC). In some embodiments, the cancer is FGF19-positive esophageal cancer, nasopharyngeal carcinoma, or ovarian cancer. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at a dose of about 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0440] PD173074 (Pfizer) is a highly potent FGFR1 inhibitor with an IC50 of ~25 nM. It also inhibits VEGF2, with an IC50 of 100-200 nM in cell-free assays. Its selectivity for FGFR1 is ~1000 times higher than that for PDGFR and c-Src. PD173074 has the following chemical structure:

[0441]

[0442] In some embodiments, this document provides compositions and treatment methods for treating cancers with FGFR dysregulation or signal transduction abnormalities, wherein said treatment comprises administering the CDK4 / 6 inhibitor and PD173074 described herein, wherein the CDK4 / 6 inhibitor and PD173074 are administered daily on a continuous schedule, for example, at least 14 days, at least 21 days, at least 28 days, at least 35 days, or longer. In some embodiments, the CDK4 / 6 inhibitor described herein is administered for 21 days daily within a 28-day cycle, and PD173074 is administered for 21 days daily within a 28-day cycle. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at a dose of about 100 mg to 200 mg, for example, 150 mg, and PD173074 is administered between about 10 mg and 500 mg, wherein the CDK4 / 6 inhibitor is administered daily for at least 21, at least 24, or 28 days in a 28-day cycle, and PD173074 is administered daily for at least 21, at least 24, or 28 days in a 28-day cycle. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at a dose of about 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0443] FIIN-2 is an irreversible pan-FGFR inhibitor with IC50 values ​​of 3.09 nM, 4.3 nM, 27 nM, and 45.3 nM for FGFR1, 2, 3, and 4, respectively. FIIN-2 has the following chemical structure:

[0444]

[0445] In some embodiments, this document provides compositions and treatments for treating cancers with FGFR-dysregulated signal transduction or abnormalities, wherein said treatment comprises administration of the CDK4 / 6 inhibitor and FIIN-2 described herein, wherein the CDK4 / 6 inhibitor and PD173074 are administered daily on a continuous schedule, for example, at least 14 days, at least 21 days, at least 28 days, at least 35 days, or longer. In some embodiments, the CDK4 / 6 inhibitor described herein is administered for 21 days daily in a 28-day cycle, and FIIN-2 is administered for 21 days daily in a 28-day cycle. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at a dose of about 100 mg to 200 mg, for example, 150 mg, and FIIN-2 is administered between about 10 mg and 500 mg, wherein the CDK4 / 6 inhibitor is administered for at least 21, at least 24, or 28 days daily in a 28-day cycle, and PD173074 is administered for at least 21, at least 24, or 28 days daily in a 28-day cycle. In some embodiments, the cancer with FGFR-dysregulated signal transduction is FGF19 overexpression or amplification. In some embodiments, the cancer is FGFR19-positive hepatocellular carcinoma, such as hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC). In some embodiments, the cancer is FGF19-positive esophageal cancer, nasopharyngeal carcinoma, or ovarian cancer. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at a dose of about 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0446] LY-2874455 is an FGFR inhibitor with anticancer chemotherapy activity. LY-2874455 inhibits cell proliferation and tumor growth in in vitro and in vivo models of various cancers, including lung cancer, gastric cancer, and multiple myeloma. LY-2874455 has the following chemical structure:

[0447]

[0448] In some embodiments, this document provides compositions and treatments for treating cancers with FGFR-dysregulated signal transduction or abnormalities, wherein said treatment comprises administration of the CDK4 / 6 inhibitor described herein and LY-2874455, wherein the CDK4 / 6 inhibitor and LY-2874455 are administered daily on a continuous schedule, for example, at least 21 days, 28 days, 35 days, or longer. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered twice daily at about 100 mg to 200 mg, for example, 150 mg, and LY-2874455 is administered twice daily at a dose between about 10 mg and 30 mg, for example, about 18 mg twice daily. In some embodiments, the cancer with FGFR-dysregulated signal transduction is FGF19 overexpression or amplification. In some embodiments, the cancer is FGFR19-positive hepatocellular carcinoma, such as hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC). In some embodiments, the cancer is FGF19-positive esophageal cancer, nasopharyngeal carcinoma, or ovarian cancer. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at approximately 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0449] Fexotetinib (BLU-554; Blueprint Medicines) is a highly selective and orally active fibroblast growth factor receptor 4 (FGFR4) inhibitor with an IC50 of 5 nM. Fexotetinib exhibits significant antitumor activity in an FGFR4-dependent hepatocellular carcinoma (HCC) model. The chemical structure of fexotetinib is as follows:

[0450]

[0451] In some embodiments, this document provides compositions and treatments for treating cancers with FGFR-dysregulated signal transduction or abnormalities, wherein said treatment comprises administration of the CDK4 / 6 inhibitor and fexotinib described herein, wherein the CDK4 / 6 inhibitor and fexotinib are administered daily on a continuous schedule, such as for at least 21 days, 28 days, 35 days, or longer. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered at about 100 mg to 200 mg twice daily, for example, 150 mg twice daily, and fexotinib is administered once daily at a dose between about 300 mg and 600 mg. In some embodiments, the cancer with FGFR-dysregulated signal transduction is FGF19 overexpression or amplification. In some embodiments, the cancer is FGFR19-positive hepatocellular carcinoma, such as hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC). In some embodiments, the cancer is FGF19-positive esophageal cancer, nasopharyngeal carcinoma, or ovarian cancer. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is used at approximately 240 mg / m³. 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0452] H3B-6527 (H3 Biomedicine) is an FGF receptor 4 inhibitor (FGFR4; IC50 = <1.2 nM). Its selectivity for FGFR4 is higher than that for FGFR1, FGFR2, and FGFR3 (IC50 = 320, 1,290, and 1,060 nM, respectively). H3B-6527 has the following chemical structure:

[0453]

[0454] In some embodiments, this document provides compositions and treatments for treating cancers with FGFR-dysregulated signal transduction or abnormalities, wherein said treatment comprises administration of the CDK4 / 6 inhibitor described herein and H3B-6527, wherein the CDK4 / 6 inhibitor and H3B-6527 are administered daily on a continuous schedule, for example, at least 21 days, 28 days, 35 days, or longer. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered at about 100 mg to 200 mg twice daily, for example, 150 mg twice daily, and H3B-6527 is administered once daily at a dose between about 300 mg and 1200 mg (e.g., 1000 mg), or at a dose between about 150 mg and 600 mg (e.g., about 500 mg) twice daily. In some embodiments, cancers with FGFR-dysregulated signal transduction are characterized by FGF19 overexpression or amplification. In some embodiments, the cancer is FGFR19-positive hepatocellular carcinoma, such as hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC). In some embodiments, the cancer with FGFR-dysregulated signal transduction is FGF19 overexpression or amplification. In some embodiments, the cancer is FGFR19-positive hepatocellular carcinoma, such as hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC). In some embodiments, the cancer is FGF19-positive esophageal cancer, nasopharyngeal carcinoma, or ovarian cancer. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at approximately 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0455] SOMCL-085 is a triple inhibitor of FGFR, VEGFR, and PDGFR. SOMCL-085 highly inhibits the activity of FGFR1-3 kinases, with IC50 values ​​of 1.8, 1.9, and 6.9 nmol / L, respectively, and shows weaker activity against FGFR4 (IC50 = 319.9 nmol / L). The chemical structure of SOMCL-085 is as follows:

[0456]

[0457] INCB062079 is a selective FGFR4 inhibitor that can inhibit tumor cell proliferation in cells with FGF19 amplification and expression (see, e.g., AACR; Cancer Res 2017; 77(13Suppl):Abstract nr 1234,PMID:32154250). In some embodiments, this document provides a method of treating cancers with FGFR-dysregulated signal transduction or abnormalities by administering the CDK4 / 6 inhibitor described herein and INCB062079, wherein the CDK4 / 6 inhibitor and INCB062079 are administered daily on a continuous schedule, for example, at least 21 days, 28 days, 35 days, or longer. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered at about 100 mg to 200 mg twice daily, for example, 150 mg twice daily, and INCB062079 is administered at least once daily at a dose between about 50 mg and 1200 mg. In some embodiments, cancers with FGFR-dysregulated signal transduction are those with FGF19 overexpression or amplification. In some embodiments, the cancer is an FGFR19-positive hepatocellular carcinoma, such as hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC). In some embodiments, the cancer is an FGF19-positive esophageal cancer, nasopharyngeal carcinoma, or ovarian cancer. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at approximately 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0458] Alonib (RPT835) is a highly potent and selective allosteric inhibitor of fibroblast growth factor receptor 2 (FGFR2), with the following structure:

[0459]

[0460] In some embodiments, this document provides compositions and treatments for treating cancers with FGFR dysregulation or signal transduction abnormalities, wherein said treatment comprises administration of the CDK4 / 6 inhibitor described herein and aronibu, wherein the CDK4 / 6 inhibitor and aronibu are administered daily, for example, days 1 to 5 of a 7-day cycle. In some embodiments, aronibu is administered on days 1 to 5 of a 7-day cycle, and the CDK4 / 6 inhibitor is administered at least once daily for 7 days. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered at about 100 mg to 200 mg twice daily, for example, 150 mg twice daily, and aronibu is administered at about 50 to 350 mg / m². 2 Between (e.g., 50 mg / m²) 2 100mg / m 2 165mg / m 2 250mg / m 2 Or 350mg / m 2 ), administered once daily. In an alternative embodiment, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at approximately 240 mg / m². 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0461] Bemarituzumab (FPA144, Five Prime Therapeutics) is an FGFR2b antibody in clinical development for targeted immunotherapy of tumors overexpressing FGFR2b. In some embodiments, this document provides a method of treating cancers with FGFR-dysregulated signaling or abnormalities by administering the CDK4 / 6 inhibitor described herein and bemarituzumab. In some embodiments, the CDK4 / 6 inhibitor is administered at least once daily for 14 days in a 14-day cycle, and bemarituzumab is administered every 14 days in a 14-day cycle. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered at about 100 mg to 200 mg twice daily, for example, 150 mg twice daily, and bemarituzumab is administered at about 0.3 mg / kg to about 15 mg / kg (e.g., about 3-10 mg) every two weeks. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is used at approximately 240 mg / m³. 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0462] MGFR1877S (Genentech) is a monoclonal antibody selective for FGFR3. In some embodiments, this document provides compositions and treatments for treating cancers with FGFR-dysregulated signal transduction or abnormalities, wherein said treatment comprises administration of the CDK4 / 6 inhibitor described herein and MGFR1877S. In some embodiments, the CDK4 / 6 inhibitor is administered at least once daily for 14 days in a 14-day cycle, and MGFR1877S is administered every 14 days in a 14-day cycle. In some embodiments, the CDK4 / 6 inhibitor is administered at least once daily for 28 days in a 28-day cycle, and MGFR1877S is administered every 28 days in a 28-day cycle. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered at about 100 mg-200 mg twice daily, for example, 150 mg twice daily, and MGFR1877S is administered at about 0.3 mg / kg to about 25 mg / kg (for example, between about 3-10 mg) every two weeks. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at about 240 mg / kg. 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0463] Wovatuzumab (B-701, Rainier Therapeutics) is an antibody that targets fibroblast growth factor receptor 3 (FGFR3). In some embodiments, this document provides compositions and treatments for treating cancers with FGFR-dysregulated signal transduction or abnormalities, wherein said treatment comprises administration of the CDK4 / 6 inhibitor described herein and vorvatuzumab. In some embodiments, the CDK4 / 6 inhibitor is administered at least once daily for 21 days in a 21-day cycle, and vorvatuzumab is administered every 21 days in a 21-day cycle. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered at about 100 mg–200 mg twice daily, for example, 150 mg twice daily, and vorvatuzumab is administered at a dose between about 20 mg / kg and about 30 mg / kg (for example, about 25 mg) every three weeks. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at about 240 mg / kg... 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0464] GSK3052230 is a soluble fusion protein formed by fusing the extracellular domain of human fibroblast growth factor receptor 1 (FGFR1) with the Fc moiety of human immunoglobulin G1 (IgG1), exhibiting antitumor and anti-angiogenic activities. In some embodiments, this document provides compositions and treatments for treating cancers with FGFR-dysregulated signal transduction or abnormalities, wherein said treatment comprises administration of the CDK4 / 6 inhibitor described herein and GSK3052230. In some embodiments, the CDK4 / 6 inhibitor is administered at least once daily for 21 days in a 21-day cycle, and GSK3052230 is administered weekly in a 21-day cycle. In some embodiments, the CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B, administered at about 100 mg–200 mg twice daily, for example, 150 mg twice daily, and GSK3052230 is administered at about 5 mg / kg to about 20 mg / kg, for example, about 5, 10, 15, or 20 mg / kg. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, compound III is administered at about 240 mg / kg. 2 For systemic, parenteral, intravenous, intramuscular, subcutaneous, or intradermal administration.

[0465] Cancers with dysregulated FGFR signaling pathways

[0466] Fibroblast growth factor receptors (FGFRs) are a subfamily of receptor tyrosine kinases that bind to fibroblast growth factor (FGF) and exert their pleiotropic effects by binding to and activating FGFRs. The FGFR family is encoded by four genes (FGFR1, FGFR2, FGFR3, and FGFR4) (see Johnson DE, Williams LT 1993. Structural and functional diversity in the FGF receptor multigene family. Adv Cancer Res 60:1–41; Mohammadi et al., 2005b. Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev 16:107–137). The extracellular domain of the FGFR consists of three immunoglobulin (Ig)-like domains (D1, D2, and D3), while the intracellular domain contains a conserved tyrosine kinase domain flanked by flexible N-terminal proximal membrane linkers and C-terminal tails (see Givol et al., 1992. Complexity of FGF receptors: Genetic basis for structural diversity and functional specificity. FASEB J 6:3362–3369). A unique feature of the FGFR is the presence of a continuous glutamate and aspartate segment in the D1-D2 linker, termed the acid box (AB). The proximal D2 and D3 links on both membranes, as well as the intermediate D2-D3 linker, are necessary and sufficient for ligand binding / specificity, while the D1 and D1-D2 linkers are involved in receptor autoinhibition (Kalinina et al., 2012. The alternatively spliced ​​acid box region plays a key role in FGF receptor autoinhibition. Structure 20:77–88).

[0467] Although encoded by different genes, the four members share high homology, with sequence identity varying from 56% to 71% (Itoh N., Ornitz DM, evolution of the Fgf and Fgfr gene families. Trends Genet. 2004; 20:563–569. doi:10.1016 / j.tig.2004.08.007). FGF binding drives FGFR dimerization; subsequently, it induces trans-autophosphorylation of the intracellular kinase domain, which in turn activates downstream signaling pathways. By triggering downstream signaling pathways, FGFR participates in a variety of important physiological processes, such as proliferation, differentiation, cell migration, and survival (Ornitz DM, Itoh N. The Fibroblast Growth Factor signaling pathway. Wiley Interdiscip. Rev.Dev.Biol. 2015; 4:215–266. doi:10.1002 / wdev.176).

[0468] The catalytic activity of the kinase domain is precisely regulated. All protein kinases (including those in the FGFR family) have two general conformations. Activation typically involves changes in the orientation of the α-C-helix in the leaflet and the orientation of the activation loop in the C-leaf. During a catalytic cycle, the activated kinase switches between open and closed conformations. In the open form, the kinase binds to MgATP and the protein substrate, while in the closed form, the kinase is activated during catalysis. Once catalysis is complete, MgADP and the phosphorylated substrate are released, and the enzyme returns to the open conformation, preparing for the next catalytic cycle (Farrell B., Breeze ALS structure, activation and dysregulation of fibroblast growth factor receptor kinases: Perspectives for clinical targeting. Biochem. Soc. Trans. 2018; 46:1753–1770. doi:10.1042 / BST20180004).

[0469] Aberrant expression of FGFR has been observed in various solid tumors, and this aberration is considered to be an oncogenic signaling pathway (Turner N., Grose R. Fibroblast growth factor signalling: From development to cancer. Nat. Rev. Cancer. 2010; 10:116–129. doi:10.1038 / nrc2780).

[0470] The compositions and treatments described herein are useful for treating hosts with cancers exhibiting dysregulation of the fibroblast growth factor receptor (FGFR) pathway signaling due to FGFR or FGF abnormalities, through combination or alternating administration of the CDK4 / 6 inhibitors described herein with FGFR inhibitors (including, but not limited to, selective FGFR inhibitors). Dysregulation of the fibroblast growth factor receptor (FGFR) pathway signaling is an emerging focus of targeted therapy for a variety of cancer types, particularly, but not limited to, urothelial carcinoma, breast cancer, non-small cell lung cancer, including squamous cell lung cancer and large cell carcinoma, gastric cancer, including gastric adenocarcinoma and intrahepatic cholangiocarcinoma. Dysregulation of FGFR signaling includes a range of FGFR family abnormalities, including but not limited to, FGFR gene amplification, FGFR overexpression, FGFR fusion, FGFR point mutations, and FGFR gene rearrangements, as well as FGF abnormalities, including but not limited to FGF overexpression or amplification, and FGF mutations. In some embodiments, this document provides compositions and treatments for treating cancers with FGFR dysregulation or signal transduction abnormalities, wherein the treatment comprises administering, in combination or alternately, the CDK4 / 6 inhibitor and the FGFR inhibitor described herein to a host, wherein the dysregulation of FGFR signal transduction is caused by one or more of the following: FGFR gene amplification, FGFR overexpression, FGFR fusion, FGFR point mutation, and FGFR gene rearrangement, or FGF mutation, overexpression, or amplification. In some embodiments, the cancer is advanced or metastatic.

[0471] A study using next-generation sequencing (NGS) on samples from approximately 5,000 patients with various cancers showed that 7.1% of the samples had FGFR abnormalities. FGFR overexpression accounted for the majority of these dysregulations (66%), followed by FGFR activating mutations (26%) and FGFR gene rearrangements or fusions (8%) (Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res. 2016; 22(1):259-67. doi:10.1158 / 1078-0432.CCR-14-3212). Overall, FGFR1 / 2 / 3 / 4 signaling dysregulation was most commonly observed in urothelial carcinoma (31.7%), breast cancer (17.4%), endometrial cancer (11.3%), and ovarian cancer (8.6%) (Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res. 2016; 22(1):259-67. doi:10.1158 / 1078-0432.CCR-14-3212). FGFR overexpression may lead to ligand-independent FGFR signaling transduction, and it is mainly caused by focal amplification.

[0472] The results indicate that there are differences in the dysregulation patterns among different cancer types and specific genes within families. Overexpression or amplification accounts for approximately 89% of all FGFR1 abnormalities (Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res. 2016; 22(1):259-67. doi:10.1158 / 1078-0432.CCR-14-3212) and has been found in approximately 16% of non-small cell lung cancer (NSCLC), including squamous cell lung cancer and large cell lung cancer (Yang W, Yao YW, Zeng JL, et al. Prognostic value of FGFR1 gene copy number inpatients with non-small cell lung cancer: a meta-analysis. J Thorac Dis.2014;6(6):803-9.doi:10.3978 / j.issn.2072-1439.2014.05.02); (Weiss J, Sos ML, Seidel D, et al., Frequent and focal FGFR1 amplification associates with therapeuticallytractable FGFR1 dependency in squamous cell lung cancer.Sci Transl Med.2010;2(62):62ra93.doi:10.1126 / scitranslmed.3001451), 6% of small cell lung cancers (Peifer M, This was confirmed in L, Sos ML et al., Integrative genome analyses identify keyomatic driver mutations of small-cell lung cancer. Nat Genet. 2012; 44(10):1104-1110. doi:10.1038 / ng.2396.

[0473] FGFR1 amplification has also been found in approximately 18% of osteosarcomas, and it is associated with sensitivity to FGFR inhibitors in preclinical in vivo models. In breast cancer, FGFR1- and / or 11q12-14 (which includes CCND1, FGF3, FGF4, and FGF19) amplification has been observed in 23% of hormone receptor-positive (HR+), 27% of HER2- amplification, and 7% of triple-negative cases, and can predict early recurrence and adverse outcomes. Many FGFR1-amplified breast cancer cell lines are addicted to FGFR1 amplification, and FGFR1 amplification can also lead to resistance to endocrine therapy.

[0474] FGFR2 amplification has been confirmed in approximately 4% of gastric cancers (Matsumoto K, Arao T, Hamaguchi T, et al., FGFR2 gene amplification and clinicopathological features in gastric cancer. Br J Cancer. 2012; 106(4):727-732. doi:10.1038 / bjc.2011.603). However, gastric and breast cancer cell lines with FGFR2 amplification are particularly sensitive to selective FGFR inhibitors, suggesting that FGFR amplification confers dependence on the FGFR signaling pathway (Pearson A, Smyth E, Babina IS, et al., High-level clonal FGFR amplification and response to FGFR inhibition in a translational clinical trial. CancerDiscov. 2016; 6(8):838-851. doi:10.1158 / 2159-8290.CD-15-1246; Campbell J, Ryan CJ, Brough R, et al., Large-scale profiling of kinase dependencies in cancer celllines. Cell Rep. 2016; 14(10):2490-2501. doi:10.1016 / j.celrep.2016.02.023). FGFR2 amplification is associated with the maintenance of tumor-initiating cells, poor prognosis, and high sensitivity to FGFR inhibitors.

[0475] FGFR3 amplification is relatively uncommon, but it has been confirmed in 3% of urothelial carcinomas (Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res. 2016; 22(1):259-67. doi:10.1158 / 1078-0432.CCR-14-3212).

[0476] Mutations in activated FGFR may lead to aberrant FGFR signaling through a variety of mechanisms, including: (i) enhanced activation of the kinase domain; (ii) ligand-independent dimerization of the receptor; and (iii) altered affinity for FGF ligands.

[0477] Activating mutations in FGFR2 occur in 12% to 14% of endometrial cancers and have been confirmed in a small percentage of squamous NSCLC, gastric cancer, and urothelial carcinoma (Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res. 2016; 22(1):259-67. doi:10.1158 / 1078-0432.CCR-14-3212); (Touat M, Ileana E, Postel-Vinay S, Andre F, Soria JC. Targeting FGFR signaling in cancer. Clin Cancer Res. 2015; 21(12):2684-2694. doi:10.1158 / 1078-0432.CCR-14-2329). For example, FGFR2 mutations in endometrial cancer are mainly composed of missense activating mutations (S252W, P253R) in the extracellular domain. In vitro and in vivo models demonstrated the selective sensitivity of FGFR2-mutant endometrial cancer to FGFR inhibitors.

[0478] Activating mutations in FGFR3 are particularly prevalent in urothelial carcinomas, occurring in up to 80% of non-muscle-invasive urothelial carcinomas, 20% of high-grade invasive urothelial carcinomas, and 5% of cervical cancers (Touat M, Ileana E, Postel-Vinay S, Andre F, Soria JC. Targeting FGFR signaling in cancer. Clin Cancer Res. 2015; 21(12):2684-2694. doi:10.1158 / 1078-0432.CCR-14-2329). Bladder urothelial carcinoma has the strongest association with FGFR signaling alterations, with up to 80% of low-grade tumors exhibiting FGFR mutations and compelling in vivo and in vitro data. The comprehensive molecular characterization of this cancer reveals a group of papillary tumors characterized by high rates of FGFR3 molecular alterations (mutations, copy number increases, fusions), which may indicate some degree of FGFR addiction. The most common activating mutations affect the extracellular (R248C, S249C) or transmembrane (G370C, S371C, Y373C, G380R, A391E) domains of proteins. Mutations in the kinase domain (N540S, K650E, K650M, K650N, K650Q, and K650T) are relatively rare.

[0479] Activating mutations in FGFR1 and FGFR4 are relatively rare, observed in pilocytic astrocytoma (FGFR1) and rhabdomyosarcoma (FGFR4) (Touat M, Ileana E, Postel-Vinay S, Andre F, Soria JC. Targeting FGFR signaling in cancer. Clin Cancer Res. 2015; 21(12):2684-2694. doi:10.1158 / 1078-0432.CCR-14-2329). Activating mutations in FGFR4 (affecting the kinase domain) have been found in 6% to 8% of rhabdomyosarcoma patients. In a comprehensive genomic analysis of 147 rhabdomyosarcoma cases, FGFR signaling was the most significantly altered pathway in both fusion-positive and fusion-negative rhabdomyosarcoma. Cell lines and explants carrying activating mutations in FGFR4 were sensitive to FGFR inhibitors.

[0480] Fusion genes are heterozygous genes formed by the rearrangement of two previously independent genes. They can occur due to translocation, chromosomal inversion, duplication, or deletion. Several fusion proteins are known to play key roles in the occurrence and development of cancer, thus representing ideal targets for rational drug design strategies.

[0481] Recent molecular screening programs and precision medicine efforts have enabled the identification of multiple fusion genes between FGFR1, -2, and -3 and multiple partners (including TACC1, TACC3, BAIAP2L1, BICC1, CASP7, and AHCYL1) in several malignancies, such as glioblastoma, urothelial carcinoma of the bladder, non-small cell lung cancer (NSCLC), and cholangiocarcinoma.

[0482] In intrahepatic cholangiocarcinoma, fusion / translocation of FGFR2 with AHCYL1 or BICC1 was described in 13.6% of cases, and these fusions were mutually exclusive with their KRAS / BRAF mutations. In vivo models demonstrated the transformative potential of these alterations and their high sensitivity to FGFR inhibitors.

[0483] FGFR2 fusions / translocations are found in approximately 14% of intrahepatic cholangiocarcinomas, and occasionally in lung, thyroid, and prostate cancers (Touat M, Ileana E, Postel-Vinay S, Andre F, Soria JC. Targeting FGFR signaling in cancer. Clin Cancer Res. 2015; 21(12):2684-2694. doi:10.1158 / 1078-0432.CCR-14-2329); (Arai Y, Totoki Y, Hosoda F et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology. 2014; 59(4):1427-1434. doi:10.1002 / hep.26890); (Wu YM, Su F, Kalyana-Sundaram S et al., Identification of targetable FGFR gene fusions indiverse cancers. Cancer Discov. 2013; 3(6):636-647. doi:10.1158 / 2159-8290.CD-13-0050. FGFR1 translocation is relatively uncommon, but has been observed in glioblastoma, breast cancer, squamous cell lung cancer and myeloproliferative syndromes (Touat M, Ileana E, Postel-Vinay S, Andre F, Soria JC. Targeting FGFR signaling in cancer. Clin Cancer Res. 2015; 21(12):2684-2694. doi:10.1158 / 1078-0432.CCR-14-2329).

[0484] FGFR3 translocation / fusion accounts for 15% to 20% of multiple myeloma and has been observed in glioblastoma and bladder cancer (Touat M, Ileana E, Postel-Vinay S, Andre F, Soria JC. Targeting FGFR signaling in cancer. Clin Cancer Res. 2015; 21(12):2684-2694. doi:10.1158 / 1078-0432.CCR-14-2329).

[0485] Fusions involving FGFR3 and TACC3 (transformed acid coil-coil protein 3) have been found in 3% to 7% of glioblastomas, 3% to 6% of urothelial carcinomas of the bladder, and other lower-frequency tumor types. In a mouse xenograft model, induction of FGFR3-TACC3 expression in human astrocytes led to the development of glioma-like tumors. In vivo, both FGFR3-TACC3-induced bladder cancer and glioblastoma are highly sensitive to specific FGFR inhibitors, suggesting an oncogenic addiction to fusion proteins. FGFR gene fusions associated with cancer development include, but are not limited to, FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, and FGFR2-CASP7.

[0486] FGF abnormalities have also been shown to play a role in the progression of cancers with dysregulated FGFR signaling. For example, FGF19 amplification has been found to be significantly associated with an increased risk of hepatocellular carcinoma (HCC) (see Raja, FGF19–FGFR4 Signaling in Hepatocellular Carcinoma. Cells. 2019 Jun; 8(6):536).

[0487] Determining the mutational status of FGFR-mutant cancers is well-known in the field. For example, the Therascreen FGFRRGQ RT-PCR kit is a real-time, reverse transcription PCR assay used to quantitatively detect two point mutations [p.R248C (c.742C>T), p.S249C (c.746C>G)] in exon 7 of fibroblast growth factor receptor 3 (FGFR3), two point map mutations [p.G370C (c.1108G>T) and p.Y373C (c.1118A>G)] in exon 10, and two fusions (FGFR3-TACC3v1 and FGFR3-TACC3v3) in RNA samples from formalin-fixed paraffin-embedded (FFPE) urothelial carcinoma tissue. This assay is used to help identify patients with urothelial carcinoma (UC) who have these alterations and are therefore eligible for treatment with BALVERSA (erdatinib). Samples were prepared artificially using the RNeasy DSP FFPE kit, followed by reverse transcription, and then automated amplification and detection on a Rotor-Gene Q MDx (USA) instrument.

[0488] In addition, direct DNA sequencing is well-known for identifying mutations in genes encoding FGFR1–4 and in non-FGFR genes that induce tumor resistance to FGFR-TKIs. Other useful mutation analysis techniques include, but are not limited to, analysis via dHPLC, DNA endonuclease (SURVEYOR) and HPLC, HRMA, massively parallel sequencing, TaqMan PCR, Cycleave PCR, fragment analysis, mutation-specific PCR, mutation-enriched PCR, ARMS, mutation-enriched ARMS TaqMan PCR, PCR-invader, and PCR-RFLP.

[0489] In the absence of tissue biopsy, plasma cell-free tumor DNA or circulating tumor DNA (ctDNA) from liquid biopsy is a potential source of tumor genetic material for FGFR mutation detection. Allele-specific PCR, scorpion amplification arrest mutation system (ARMS) PCR, droplet digital PCR (ddPCR), and next-generation sequencing (NGS) are the most commonly used ctDNA mutation detection techniques and are well-known in the field. See Veldore et al., Lung Cancer (Auckl). 2018; 9:1–11; Bordi et al., Transl Lung Cancer Res. 2015; 4(5):584-597; Fenizia et al., Future Oncol. 2015; 11(11):1611-1623; Mao et al., Medicine. 2015; 94(21):e775. doi:10.1097 / MD.0000000000000775; Marchetti et al., J Thorac Oncol. 2015; 10(10):1437-1443; Sholl et al., Arch Pathol Lab Med. doi:10.5858 / arpa.2016-0163-SA; Sorber et al., Lung Cancer. 2016 May 4. pii:S0169-5002(16)30312-9. doi:10.1016 / j.lungcan.2016.04.026;Westwood et al., Health Technol Assess.2014;18(32):1-166;Lindeman et al., J ThoracOncol.2013;8(7):823-859;Socinski et al., Clin Lung Cancer.2010;11(3):149-159, all of which are incorporated herein by reference. Determining the amplification or overexpression status of FGFR is also well known in the art, and commercial assays are available for determining overexpression and / or amplification status. For example, FGFR FISH assays are designed to detect FGFR amplification or translocation. For example, an FGFR locus is reported as amplified when the ratio of FGFR to the test locus exceeds a threshold or when the average copy number of the FGFR locus is observed per tumor nucleus.See, for example, Schildhaus HU, Heukamp LC, Merkelbach-Bruse S et al.: Definition of a fluorescence in-situ hybridization score identifies high-and-low-level FGFR1 amplification types in squamous cell lung cancer. Mod Pathol 2012 Nov; 25(11):1473-1480; see also Liang et al., 2012 Trends Pharmacol Sci 33.

[0490] Specific cancers suitable for targeting with the compositions and treatments described herein include those with FGFR abnormalities, including urothelial carcinoma, bladder cancer, breast cancer, endometrial cancer, ovarian cancer, osteosarcoma, primary unknown carcinoma, glioma, glioblastoma, liver cancer including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma, gastric cancer including gastric adenocarcinoma, non-small cell lung cancer, small cell lung cancer, rhabdomyosarcoma, pancreatic exocrine carcinoma, colorectal cancer, renal cell carcinoma, neuroendocrine carcinoma, head and neck (squamous cell) carcinoma, melanoma, leiomyosarcoma, cervical cancer, and sarcoma. In some embodiments, the cancer is advanced or metastatic.

[0491] In some embodiments, this document provides compositions and treatments for treating cancers with FGFR dysregulation or abnormal signal transduction caused by FGFR1 abnormalities, wherein the treatment comprises administering to the host a combination of the CDK4 / 6 inhibitor described herein and a selective FGFR inhibitor. In some embodiments, the FGFR inhibitor is selected from the following: erdatinib, pemitinib, infeltilatinib, AZD4547, fabatinib, deratinib, Debio1347, PRN1371, FIIN,2, GSK3052230, and PD173074. In some embodiments, the FGFR1 abnormality is FGFR1 overexpression or amplification, FGFR1 mutation, FGFR1 translocation, or FGFR1 fusion. In some embodiments, the cancer is selected from non-small cell lung cancer, including squamous cell lung cancer, large cell lung cancer, and lung adenocarcinoma; breast cancer, including hormone receptor-positive cancers such as estrogen receptor-positive breast cancer, HER2-positive or HER2-amplified breast cancer; osteosarcoma; pilocytic astrocytoma; and glioblastoma. In some embodiments, the cancer is non-small cell lung cancer with FGFR1 amplification. In some embodiments, the cancer is small cell lung cancer with FGFR1 amplification. In some embodiments, the cancer is ER+, HER2+, HER2 amplified breast cancer with FGFR1 amplification. In some embodiments, the cancer is triple-negative breast cancer with FGFR1. In some embodiments, the cancer is osteosarcoma with FGFR1 amplification. In some embodiments, the cancer is pilocytic astrocytoma with FGFR mutation. In some embodiments, the cancer is glioblastoma, non-small cell lung cancer (NSCLC), and cholangiocarcinoma with FGFR1 translocation or rearrangement. In some embodiments, the cancer is metastatic or advanced. In some embodiments, the applied CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, the applied CDK4 / 6 inhibitor is compound VI.

[0492] In some embodiments, this document provides compositions and treatments for treating cancers with FGFR dysregulation or abnormal signal transduction caused by FGFR2 abnormalities, wherein the treatment comprises administering to the host a combination of the CDK4 / 6 inhibitor described herein and a selective FGFR inhibitor. In some embodiments, the FGFR inhibitor is selected from the following: erdatinib, pemitinib, infeltilatinib, AZD4547, fabatinib, deratinib, LY287445, Debio1347, PRN1371, alonibuprofen, bemarituzumab, and FIIN-2. In some embodiments, the FGFR2 abnormality is FGFR2 overexpression or amplification, FGFR2 mutation, or FGFR2 translocation or fusion. In some embodiments, the cancer is selected from gastric cancer, breast cancer, including but not limited to hormone receptor-positive cancers such as estrogen receptor-positive breast cancer, HER2-positive or HER2-amplified breast cancer such as ER+ / HER2-amplified breast cancer, endometrial cancer, non-small cell lung cancer including squamous cell lung cancer, gastric cancer, urothelial carcinoma, intrahepatic cholangiocarcinoma, thyroid cancer, and prostate cancer. In some embodiments, the cancer is gastric cancer, for example, gastric adenocarcinoma, and the cancer has FGFR2 amplification. In some embodiments, the cancer is endometrial cancer, non-small cell lung cancer, or gastric adenocarcinoma, and the cancer has an FGFR2 mutation. In some embodiments, the FGFR2 mutation is selected from S252W substitution and P253R substitution. In some embodiments, the cancer is intrahepatic cholangiocarcinoma, non-small cell lung cancer, or thyroid cancer, and the cancer has an FGFR2 fusion. In some embodiments, the FGFR2 fusion is FGFR2-BICC1, FGFR2-AHCYL1 (adenosine homocysteine-like 1) fusion, or FGFR2-CASP7 (caspase 7) fusion. In some embodiments, the applied CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some embodiments, the applied CDK4 / 6 inhibitor is compound VI.

[0493] In some embodiments, this document provides compositions and treatments for treating cancers with FGFR dysregulation or abnormal signal transduction caused by FGFR3 abnormalities, wherein the treatment comprises administering to the host a combination of the CDK4 / 6 inhibitor described herein and a selective FGFR inhibitor. In some embodiments, the FGFR inhibitor is selected from the following: erdatinib, pemitinib, inflavinib, AZD4547, fobatinib, deratinib, LY287445, Debio1347, PRN1371, MGFR1877S, vorvastatinib, and FIIN-2. In some embodiments, the FGFR3 abnormality is FGFR3 overexpression or amplification, FGFR3 mutation, FGFR3 translocation, or FGFR3 fusion. In some embodiments, the cancer is selected from cervical cancer, urothelial carcinoma, glioblastoma, and multiple myeloma. In some embodiments, the cancer is cervical cancer, and the cancer has an FGFR3 mutation. In some embodiments, the FGFR3 mutation is selected from one of the following substitutions: R248C, S249C, G370C, S371C, Y373C, G380R, A391E, N540S, K650E, K650M, K650N, K650Q, and K650T. In some embodiments, the cancer is glioblastoma or multiple myeloma, and the cancer has an FGF translocation or an FGFR fusion. In some embodiments, the FGFR3 fusion is an FGFR3 and TACC3 (converted acidic coil-like protein 3) fusion or an FGFR3-BAIAP2L1 (BAI1-associated protein 2-like 1 fusion) fusion. In some embodiments, the cancer is advanced or metastatic. In some embodiments, the applied CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B. In alternative embodiments, the CDK4 / 6 inhibitor is compound III. In some implementations, the CDK4 / 6 inhibitor applied is compound VI.

[0494] In some embodiments, this document provides compositions and treatments for treating cancers with FGFR dysregulation or signal transduction abnormalities caused by FGFR4 or FGF19 abnormalities, wherein the treatment comprises administering to the host a combination of the CDK4 / 6 inhibitor described herein and a selective FGFR inhibitor. In some embodiments, the FGFR inhibitor is selected from the following: infelterinib, AZD4547, fobatinib, deratinib, LY287445, INCB062079, BLU9931, H3-6527, fexotinib, Debio134, PRN1371, robrutinib, and FIIN-2. In some embodiments, the FGFR4 abnormality is FGFR4 overexpression or amplification, FGFR4 mutation, FGFR4 translocation, or FGFR4 fusion. In some embodiments, the cancer is selected from liver cancer, including hepatocellular carcinoma, rhabdomyosarcoma, breast cancer, including hormone ER+ / HER2-positive or HER2-amplified breast cancer, endometrial cancer, and ovarian cancer. In some embodiments, the cancer is rhabdomyosarcoma and has an FGFR4 mutation. In some embodiments, the cancer is hepatocellular carcinoma and has abnormal fibroblast growth factor 19 (FGF19) signaling transduction via FGFR4 (FGR19 positive). In some embodiments, the cancer has FGF19 overexpression or amplification. In some embodiments, the cancer is hepatocellular carcinoma (HCC) and has FGF19 overexpression or amplification. In some embodiments, the cancer is advanced or metastatic. In some embodiments, the applied CDK4 / 6 inhibitor is compound I, compound IA, or compound IA, type B. In alternative embodiments, the CDK4 / 6 inhibitor is compound III.

[0495] In some implementations, the cancer to be treated is CDK4 / 6 replication-dependent. CDK4 / 6 replication-dependent cancers require CDK4 / 6 activity for replication or proliferation. CDK4 / 6 replication-dependent cancers typically have intact and functional Rb pathways and / or increased expression of CDK4 / 6 activators (cyclin D) and / or d-type cyclin activation features (DCAFs), including CCND1 translocation, loss of the CCND1-3 3'UTR, and amplification of CCND2 or CCND3 (see Gong et al., Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK5 inhibitor abemaciclib. Cancer Cell. 2017; 32(6):761-76). Wild-type RB and CCNE1 / 2 tumors and tumors with one of the aforementioned DCAFs are generally classified as "CDK4 / 6 dependent".

[0496] In any of the embodiments described above, the cancer progresses during or after at least one prior chemotherapy therapy, such as platinum-based chemotherapy, such as cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatinium tetranitrate, phenanthreneplatin, pyridine, or saxaplatin.

[0497] In some embodiments described above, the cancer to be treated does not have mutations mutually exclusive with FGFR mutations, such as KRAS or BRAF mutations. In some embodiments described above, other anticancer active agents are administered to the host. In some embodiments, the other active agents are immunomodulators or checkpoint inhibitors. In one aspect of this embodiment, the bioactive agent is an immunomodulator, including but not limited to checkpoint inhibitors, including, as non-limiting examples, PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, T cell-activated V-domain Ig repressor (VISTA) inhibitors, TIGIT inhibitors, Siglec-15 inhibitors, B7-H3 (CD272) inhibitors, BTLA inhibitors (CD272), small molecules, peptides, nucleotides, or other inhibitors. In some aspects, the immunomodulator is an antibody, such as a monoclonal antibody.

[0498] In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor that inhibits immunosuppression by binding to the PD-1 receptor, blocking the interaction between PD-1 and PD-L1. In some embodiments, the immune checkpoint inhibitor is a PD-1 immune checkpoint inhibitor selected from, but not limited to, nivolumab. Pembrolizumab Pidtilimab (Medivation) AMP-224 (Amplimmune); Sassafranumab (PF-06801591; Pfizer), Spartazumab (PDR001; Novartis), Cimipril ( REGN2810 (Regeneron), reverlimumab (MGA012 (MacroGenics), tislelizumab (BGB-A317 (BeiGene), camrelizumab (SHR-1210 (Jiangsu Hengrui Medicine Co., Ltd. and Incyte), and dotalimumab (TSR-042 (Tesaro)).

[0499] In some embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor, which inhibits immunosuppression by binding to the PD-L1 receptor, blocking the interaction between PD-1 and PD-L1. PD-L1 inhibitors include, but are not limited to, atezolizumab (…).

[0500] Genentech, Dvalumab ( AstraZeneca; Averumab ( Merck, emvelimumab (KN035; Alphamab), BMS-936559 (Bristol-Myers Squibb), lodalimumab (LY3300054; Eli Lilly), cochilimumab (CK-301; Checkpoint Therapeutics), sugemalimab (CS-1001; Cstone Pharmaceuticals), adebenonemab (SHR-1316; Jiangsu HengRui Medicine), CBT-502 (CBT Pharma), and BGB-A333 (BeiGene).

[0501] In some embodiments, the immune checkpoint inhibitor is a PD-L1 / VISTA inhibitor. PD-L1-VISTA inhibitors include, but are not limited to, CA-170 (Curis Inc.). In some embodiments, the immune checkpoint inhibitor is a VISTA immune checkpoint inhibitor. VISTA inhibitors include, but are not limited to, JNJ-61610588 (Johnson & Johnson).

[0502] In one aspect of this implementation, the immune checkpoint inhibitor is a CTLA-4 immune checkpoint inhibitor that binds to CTLA-4 and inhibits immunosuppression. CTLA-4 inhibitors include, but are not limited to, ipilimumab (…). Bristol Myers Squibb; AstraZeneca / MedImmune; Zeflimab (AGEN1884; Agenus); and Agen2041 (Agenus).

[0503] In another embodiment, the immune checkpoint inhibitor is a LAG-3 immune checkpoint inhibitor. Examples of LAG-3 immune checkpoint inhibitors include, but are not limited to, renalalimab (BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimodα (IMP321; Prima BioMed), ramucirumab (LAG525; Novartis), MK-4280 (Merck), REGN3767 (Regeneron), TSR-033 (Tesaro), BI754111 (Bohringer Ingelheim), and Sym022 (Symphogen). Other examples include the dual PD-1 and LAG-3 inhibitor terpolimbab (MGD013; MacroGenics) and the dual PD-L1 and LAG-3 inhibitor FS118 (F-Star).

[0504] In another aspect of this implementation, the immune checkpoint inhibitor is a TIM-3 immune checkpoint inhibitor. TIM-3 inhibitors include, but are not limited to, TSR-022 (Tesaro), MBG453 (Novartis), Sym023 (Symphogen), INCAGN2390 (Incyte), LY3321367 (Eli Lilly and Company), BMS-986258 (BMS), SHR-1702 (Jiangsu Hengrui), and RO7121661 (Roche).

[0505] In another aspect of this embodiment, the immune checkpoint inhibitor is a TIGIT (a T-cell immune receptor having Ig and ITIM domains) immune checkpoint inhibitor. TIGIT immune checkpoint inhibitors include, but are not limited to, MK-7684 (Merck), Etigilimab / OMP-313M32 (OncoMed), tireliumab / MTIG7192A / RG-6058 (Genentech), BMS-986207 (BMS), AB-154 (Arcus Biosciences), and ASP-8374 (Potenza).

[0506] Other immune checkpoint inhibitors used in the present invention as described herein include, but are not limited to, B7-H3 / CD276 immune checkpoint inhibitors, such as enoxolumab (MGA217, Macrogenics) and MGD009 (Macrogenics). 131 I-8H9 / omburtamab (Y-mabs) and I-8H9 / omburtamab (Y-mabs), indoleamine 2,3-dioxygenase (IDO) immune checkpoint inhibitors such as Indoximod and INCB024360, cytotoxic immunoglobulin-like receptor (KIR) immune checkpoint inhibitors such as Lirilumab (BMS-986015), and carcinoembryonic antigen cell adhesion molecule (CEACAM) inhibitors (e.g., CEACAM-1, -3, and / or -5). Exemplary anti-CEACAM-1 antibodies, such as monoclonal antibodies 34B1, 26H7, and 5F4, are described in WO 2010 / 125571, WO 2013 / 082366, and WO 2014 / 022332; or recombinant forms thereof, as described in, for example, US 2004 / 0047858, US Patent No. 7,132,255, and WO 99 / 052552. In other embodiments, the anti-CEACAM antibody binds to CEACAM-5, as described, for example, in Zheng et al., PLoS One. Sep 2, 2010; 5(9).pii:e12529 (DOI:10:1371 / journal.pone.0021146), or cross-reacts with CEACAM-1 and CEACAM-5, as described, for example, in WO 2013 / 054331 and US 2014 / 0271618.

[0507] Other checkpoint inhibitors can be molecules that target B and T lymphocyte attenuation molecules (BTLA), such as those described in Zhang et al., Monoclonal antibodies to Band T lymphocyte attenuator (BTLA) have no effect on in vitro B cell proliferation and act to inhibit in vitro T cell proliferation when presented in a cis, but not trans, format relative to the activating stimulus, Clin Exp Immunol. 2011 Jan; 163(1):77–87, and TAB004 / JS004 (Junshi Biosciences).

[0508] In another embodiment, the immune checkpoint inhibitor is a sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) inhibitor, including, but not limited to, NC318 (anti-Siglec-15 mAb).

[0509] Pharmaceutical compositions and dosage forms

[0510] Any compound used in the compositions and treatments disclosed herein may be administered as a pure chemical, but more generally as a pharmaceutical composition comprising an effective amount for a host (typically a human) requiring such treatment for any of the conditions described herein. Therefore, this disclosure provides pharmaceutical compositions for use in the methods described herein, comprising an effective amount of the compound or a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier, for any of the uses described herein. The pharmaceutical composition may comprise the compound or salt as the sole active agent, or, in alternative embodiments, the compound and at least one other active agent.

[0511] In some embodiments, the pharmaceutical composition is in a dosage form comprising about 0.0005 mg to about 2000 mg, about 0.001 mg to about 1000 mg, about 0.001 mg to about 600 mg, or about 0.001 mg to about 1, 5, 10, 15, 20, 25, 50, 100, 200, or 300 mg of the active compound. In another embodiment, the pharmaceutical composition is in a dosage form comprising about 0.01 mg to about 1, 5, 10, 15, 20, 25, 50, or 100 mg, about 0.05 mg to about 1, 5, 10, 15, 20, 25, 50, or 100 mg, about 0.1 mg to about 1, 5, 10, 15, 20, 25, or 50 mg, about 0.02 mg to about 1, 5, 10, 15, 20, 25, or 50 mg, or about 0.5 mg to about 1, 5, 10, 15, 20, 25, or 50 mg of the active compound. In another embodiment, the pharmaceutical composition is in a dosage form comprising about 0.01 mg to about 10 mg, about 0.05 mg to about 8 mg, or about 0.05 mg to about 6 mg, or about 0.05 mg to about 5 mg of the active compound. In another embodiment, the pharmaceutical composition is in a dosage form comprising about 0.1 mg to about 10 mg, about 0.5 mg to about 8 mg, about 0.5 mg to about 6 mg, or about 0.5 mg to about 5 mg of the active compound. A non-limiting example is a dosage form having at least about 0.0005, 0.001, 0.01, 0.1, 1, 2.5, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of the active compound or a salt thereof. An optional non-limiting example is a dosage form having no more than about 0.01, 0.1, 1, 2.5, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of the active compound or a salt thereof.

[0512] In some embodiments, one or more of the compounds disclosed herein are administered once daily (QD), twice daily (BID), or three times daily (TID). In some embodiments, the compounds disclosed herein or used as described are administered at least once daily for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, or for a longer period, or according to alternative schedules as described herein.

[0513] In some embodiments, one or more of the compounds used herein are administered once, twice, three times, or four times daily.

[0514] In some embodiments, one or more compounds used herein are administered orally once daily. In some embodiments, one or more compounds used herein are administered orally twice daily. In some embodiments, one or more compounds used herein are administered orally three times daily. In some embodiments, one or more compounds used herein are administered orally four times daily.

[0515] In some embodiments, one or more compounds used herein are administered intravenously once daily. In some embodiments, one or more compounds used herein are administered intravenously twice daily. In some embodiments, one or more compounds used herein are administered intravenously three times daily. In some embodiments, one or more compounds used herein are administered intravenously four times daily.

[0516] In some embodiments, one or more compounds used herein are administered in a manner that includes treatment breaks between treatment cycles. For example, one or more compounds may have treatment breaks of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle.

[0517] In other aspects, the present invention provides administration of a pharmaceutical composition comprising a therapeutically effective amount of a selective CDK4 / 6 inhibitor selected from: compound I, compound II, compound III, compound IV, compound V, compound VI, or a pharmaceutically acceptable salt thereof, and administration of a pharmaceutical composition comprising an effective amount of an FGFR inhibitor, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants, excipients, or carriers. Such excipients include liquids such as water, saline, glycerin, polyethylene glycol, hyaluronic acid, ethanol, etc.

[0518] In some embodiments, this document provides a pharmaceutical composition comprising a therapeutically effective amount of a selective CDK4 / 6 inhibitor selected from: compound I, compound II, compound III, compound IV, compound V, compound VI, or a pharmaceutically acceptable salt thereof, and an effective amount of an FGFR inhibitor or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants, excipients, or carriers. In some embodiments, the FGFR inhibitor is selected from: erdatinib, infeltilatinib, pemitinib, AZD4547, fabatinib (TAS-120), deratinib, robrutinib, LY287445, INCB062079, BLU9931, PRN1371, FIIN-2, PD173074, H3B-6527, fexotinib, alonib, and Debio1347. The pharmaceutical composition may comprise a molar ratio of a CDK4 / 6 inhibitor and an FGFR inhibitor. In a non-limiting illustrative embodiment, the pharmaceutical composition may contain a CDK4 / 6 inhibitor and an FGFR inhibitor in a molar ratio of up to about 0.5:1, about 1:1, about 2:1, about 3:1, or about 1.5:1 to about 4:1.

[0519] Excipients suitable for non-liquid formulations are also known to those skilled in the art. Pharmaceutically acceptable excipients and salts are discussed extensively in Remington's Pharmaceutical Sciences, 18th edition (Easton, Pennsylvania: Mack Publishing Company, 1990).

[0520] In addition, auxiliary substances, such as wetting agents or emulsifiers, biological buffers, and surfactants, can be present in these media. Biological buffers can be any pharmacologically acceptable solution that provides the formulation with the required pH, i.e., a pH value within a physiologically acceptable range. Examples of buffer solutions include saline, phosphate-buffered saline, Tris-buffered saline, and Hank-buffered saline.

[0521] Depending on the intended method of administration, the pharmaceutical composition may be in solid, semi-solid, or liquid dosage form, such as tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions, etc., preferably in a unit dosage form suitable for a precise single-dose administration. The composition will comprise an effective amount of the selected drug combined with a pharmaceutically acceptable carrier, and may also include other pharmaceutical agents, adjuvants, diluents, buffers, etc.

[0522] In general, the compositions of this disclosure will be administered in a therapeutically effective amount via any acceptable method of administration. Suitable dosage ranges depend on a variety of factors, such as the severity of the disease to be treated, the patient's age and relative health condition, the potency of the compound used, the route and form of administration, the indication for which administration is intended, and the preferences and experience of the physician involved. Those skilled in the art who treat such diseases will be able to determine the therapeutically effective amount of the compositions of this disclosure for a given disease based on their personal knowledge and the disclosure of this application without excessive experimentation.

[0523] Therefore, the compositions disclosed herein can be administered as pharmaceutical preparations, including those suitable for oral (including oral and sublingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous, and intravenous) administration, or in forms suitable for inhalation or insufflation. Preferred administration methods are intravenous or oral, using convenient daily dosing regimens that can be adjusted according to the degree of discomfort.

[0524] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. For example, pharmaceutically applicable liquid compositions can be prepared by dissolving and dispersing the active compound as described herein and optional pharmaceutical excipients in excipients such as water, saline, aqueous glucose solution, glycerol, ethanol, etc., to form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc., for example, sodium acetate, sorbitol monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc. Practical methods for preparing such formulations are known to those skilled in the art, or will be obvious; see, for example, Remington's Pharmaceutical Sciences cited above.

[0525] In another embodiment, a penetration enhancer excipient is used, including polymers such as: polycationic (chitosan and its quaternary ammonium derivatives, poly-L-arginine, amination gelatin); polyanionic (N-carboxymethyl chitosan, polyacrylic acid); and thiolized polymers (carboxymethyl cellulose-cysteine, polycarbofil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugate).

[0526] For oral administration, the composition will typically be in the form of tablets, capsules, soft capsules, or may be an aqueous or non-aqueous solution, suspension, or syrup. Tablets and capsules are preferred forms for oral administration. Tablets and capsules for oral administration may contain one or more common carriers, such as lactose and corn starch. Lubricants, such as magnesium stearate, are often added. Typically, the compositions of this disclosure can be combined with oral, non-toxic, pharmaceutically acceptable inert carriers, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. In addition, suitable binders, lubricants, disintegrants, and colorants may be incorporated into the mixture when desired or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth, or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. The lubricants used in these formulations include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, and xanthan gum.

[0527] When using liquid suspensions, the active agent can be combined with any orally administered, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol water, etc., as well as emulsifiers and suspending agents. Flavoring agents, coloring agents, and / or sweeteners may also be added if necessary. Other optional components for incorporation into the oral formulations described herein include, but are not limited to, preservatives, suspending agents, thickeners, etc.

[0528] Parenteral preparations can be prepared in conventional forms, as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in a liquid prior to injection, or as emulsions. Preferably, sterile injectable suspensions are formulated using suitable carriers, dispersants or wetting agents, and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in acceptable non-toxic parenteral diluents or solvents. Acceptable carriers and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile, non-volatile oils, fatty esters, or polyols are typically used as solvents or suspension media. Additionally, parenteral administration may involve the use of sustained-release or continuous-release systems to maintain a constant dose level.

[0529] Parenteral administration includes intra-articular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and includes aqueous and non-aqueous isotonic sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives. Administration via certain parenteral routes may include introducing the formulations of this disclosure into a patient through a needle or catheter propelled by a sterile syringe or some other mechanical device such as a continuous infusion system. The formulations provided by this disclosure can be administered using a syringe, injector, pump, or any other device known in the art for parenteral administration.

[0530] Preferably, the sterile injectable suspension is formulated using suitable carriers, dispersants or wetting agents, and suspending agents according to techniques known in the art. The sterile injectable formulation may also be a sterile injectable solution or a suspension in a sterile parenteral acceptable diluent or solvent. Acceptable media and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile, non-volatile oils, fatty esters, or polyols are commonly used as solvents or suspension media. Additionally, parenteral administration may involve the use of sustained-release or continuous-release systems to maintain a constant dose level.

[0531] The formulations for parenteral administration according to this disclosure include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or carriers are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. They can be sterilized, for example, by filtration through a bacterial trap filter, by adding a bactericide to the composition, by irradiating the composition, or by heating the composition. They can also be prepared immediately before use using sterile water or some other sterile injectable medium.

[0532] A sterile injectable solution is prepared by introducing a desired amount of one or more of the compounds disclosed herein, along with various other ingredients listed above (as needed), into a suitable solvent, followed by filtration and sterilization. Typically, dispersants are prepared by introducing various sterilized active ingredients into a sterile medium containing a basic dispersion medium and other desired ingredients from those listed above. In the case of sterile powders used to prepare sterile injectable solutions, preferred methods of preparation include vacuum drying and freeze-drying techniques, which produce a powder of the active ingredient plus any other desired ingredients from its previously sterile filtered solution. Thus, for example, a parenteral composition suitable for injection is prepared by stirring 10 vol% propylene glycol and water with 1.5 wt% active ingredient. The solution is isotonicized with sodium chloride and sterilized.

[0533] Alternatively, the pharmaceutical compositions of this disclosure can be administered rectally as suppositories. These can be prepared by mixing the pharmaceutical preparation with a suitable, non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0534] Each composition is delivered to the host in a pharmaceutically or therapeutically effective amount. The precise effective amount varies from host to host and depends on species, age, patient size and health status, the nature and extent of the condition being treated, the advice of the treating physician, and the choice of therapeutic agent or combination of therapeutic agents for administration. The effective amount for a given situation can be determined through routine experiments. For the purposes of this disclosure, the therapeutic amount can be, for example, in the range of at least one dose of about 0.01 mg / kg to about 250 mg / kg body weight (more preferably about 0.1 mg / kg to about 10 mg / kg). The host may be administered as many doses as needed to reduce and / or alleviate the signs, symptoms, or cause of the condition in question, or to induce any other desired changes in the biological system. When necessary, enteric-coated formulations suitable for sustained-release or controlled-release administration of the active ingredient can be prepared.

[0535] The therapeutically effective dose of any active compound described herein will be determined by a healthcare professional based on the patient's condition, body size, age, and route of delivery. In one non-limiting embodiment, a dose of about 0.1 to about 200 mg / kg is therapeutically effective, all weights being calculated based on the weight of the active compound, including in cases where saline is used. In some embodiments, the dose may be the amount of compound required to provide serum concentrations of the active compound up to about 10 nM, 50 nM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, 1 μM, 5 μM, 10 μM, 20 μM, 30 μM, or 40 μM.

[0536] In some embodiments, the pharmaceutical composition is a dosage form containing about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of an active compound and optionally about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of another active agent, or as otherwise described herein. Examples of dosage forms have at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 100, 150, 200, 250, 300, 400, 500, 600, 700, or 750 mg of the active compound or a salt thereof.

[0537] Pharmaceutical formulations are preferably unit dosage forms. In this form, the formulation can be subdivided into unit doses containing appropriate amounts of the active ingredient. A unit dosage form can be a packaged formulation containing discrete amounts of the formulation, such as tablets, capsules, and powders packaged in vials or ampoules. Furthermore, the unit dosage form itself can be a capsule, tablet, sachets, or lozenge, or it can be any appropriate quantity of these in any packaging form.

[0538] The methods disclosed herein provide for the administration of the CDK4 / 6 inhibitor and the FGFR inhibitor described herein. In some embodiments, the CDK4 / 6 inhibitor is administered at least once daily on a continuous administration schedule, i.e., for at least 7 days, at least 14 days, at least 21 days, at least 28 days, at least 35 days, at least 42 days, at least 56 days, or longer, and the FGFR inhibitor is also administered at least once daily on a continuous administration schedule, i.e., for at least 7 days, at least 14 days, at least 21 days, at least 28 days, at least 35 days, at least 42 days, at least 56 days, or longer.

[0539] In some implementations, the FGFR inhibitor is administered only for a portion of each cycle. For example, in some implementations, the FGFR inhibitor is administered at least once daily for the first 5 days of a 7-day cycle, the first 14 days of a 21-day cycle, and the first 21 days of a 28-day cycle, and the CDK4 / 6 inhibitor is administered at the same schedule, wherein the cycle is repeated once or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more times. Alternatively, the FGFR inhibitor is administered only for a portion of each cycle, for example, at least once daily for the first 5 days of a 7-day cycle, the first 14 days of a 21-day cycle, and the first 21 days of a 28-day cycle, and the CDK4 / 6 inhibitor is administered at least once daily on each day of the cycle, for example, day 7 of a 7-day cycle, day 14 of a 14-day cycle, day 21 of a 21-day cycle, or day 28 of a 28-day cycle, wherein the cycle is repeated once or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more times.

[0540] In a further alternative implementation, the FGFR inhibitor may be administered once, twice, or three times within a cycle, for example, once a week within a 21-day cycle, and the CDK4 / 6 inhibitor may be administered at least once a day on each day of the cycle.

[0541] In a further alternative implementation, the FGFR inhibitor is administered according to a set administration schedule, for example, at least once a day for the first 5 days of a 7-day cycle, the first 14 days of a 21-day cycle, the first 21 days of a 28-day cycle, or every day of a 28-day cycle, and the CDK4 / 6 inhibitor is administered intermittently, for example, once every other day, three times a week, once a week, once every two weeks, once every three weeks, or once every 28 days, wherein the cycle is repeated once or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times.

[0542] In some alternative implementations, the CDK4 / 6 inhibitor is administered at least once daily following the administration of the FGFR inhibitor.

[0543] Embodiments

[0544] The applications of the compositions and methods described herein include at least the following:

[0545] 1. A composition, drug, or treatment for treating a host with non-small cell lung cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by FGFR1 or FGFR2 abnormalities, wherein the treatment comprises administering an effective amount of a short-acting CDK4 / 6 inhibitor to the host and administering an effective amount of a selective fibroblast growth factor receptor (FGFR) inhibitor to the host, wherein the CDK4 / 6 inhibitor is selected from compounds I-VI or pharmaceutically acceptable salts thereof.

[0546] 2. The composition, drug, or treatment described in Embodiment 1, wherein the non-small cell lung cancer has an FGFR1 abnormality.

[0547] 3. The composition, drug, or treatment of any one of embodiments 1 or 2, wherein the FGFR1 abnormality is the result of FGFR1 mutation, FGFR1 overexpression or amplification, or FGFR1 translocation or fusion.

[0548] 4. The composition, drug, or treatment described in Embodiment 2, wherein the FGFR1 abnormality is FGFR1 overexpression or amplification.

[0549] 5. The composition, drug, or treatment described in Embodiment 1, wherein the non-small cell lung cancer has an FGFR2 abnormality.

[0550] 6. The composition, drug, or treatment of any one of embodiments 1 to 5, wherein the FGFR2 abnormality is the result of FGFR2 mutation, FGFR2 overexpression or amplification, or FGFR2 translocation or fusion.

[0551] 7. The composition, drug, or treatment described in Embodiment 6, wherein the FGFR2 abnormality is FGFR1 overexpression or amplification.

[0552] 8. The composition, drug, or treatment of any one of embodiments 1 to 7, wherein the non-small cell lung cancer is large cell lung cancer.

[0553] 9. The composition, drug, or treatment of any one of embodiments 1 to 7, wherein the non-small cell lung cancer is squamous cell carcinoma.

[0554] 10. The composition, drug, or treatment of any one of embodiments 1 to 9, wherein the selective FGFR inhibitor is selected from the following: erdatinib, pemitinib, inflistatinib, fubatinib, deratinib, LY287445, Debio1347, PRN1371, alonib, bemarituzumab, GSK3052230, and FIIN-2 or pharmaceutically acceptable salts thereof.

[0555] 11. The composition, drug, or treatment of any one of embodiments 1 to 10, wherein the CDK4 / 6 inhibitor is compound I, or a pharmaceutically acceptable salt thereof.

[0556] 12. The composition, drug, or treatment of any one of embodiments 1 to 10, wherein the CDK4 / 6 inhibitor is compound IA.

[0557] 13. The composition, drug, or treatment of embodiment 12, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2°, and 22.4±0.2°.

[0558] 14. The composition, drug, or treatment of any one of embodiments 1 to 10, wherein the CDK4 / 6 inhibitor is compound III, or a pharmaceutically acceptable salt thereof.

[0559] 15. The composition, drug, or treatment of any one of embodiments 1 to 14, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 14 consecutive days or 21 consecutive days.

[0560] 16. The composition, drug, or treatment of any one of embodiments 1 to 14, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 28 consecutive days.

[0561] 17. The composition, drug, or treatment of any one of embodiments 1 to 14, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 35 consecutive days.

[0562] 18. The composition, drug, or treatment of any one of embodiments 1 to 14, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 56 consecutive days.

[0563] 19. The composition, drug, or treatment of any one of embodiments 1 to 18, wherein the FGFR inhibitor is administered at least once daily for at least 14 consecutive days or 21 consecutive days.

[0564] 20. The composition, drug, or treatment of any one of embodiments 1 to 18, wherein the FGFR inhibitor is administered at least once daily for at least 28 consecutive days.

[0565] 21. The composition, drug, or treatment of any one of embodiments 1 to 18, wherein the FGFR inhibitor is administered at least once daily for at least 35 consecutive days.

[0566] 22. The composition, drug, or treatment of any one of embodiments 1 to 18, wherein the FGFR inhibitor is administered at least once daily for at least 56 consecutive days.

[0567] 23. The composition, drug, or treatment of any one of embodiments 1 to 22, wherein the host has not been treated with the CDK4 / 6 inhibitor at the time of the first administration of the CDK4 / 6 inhibitor.

[0568] 24. The composition, drug, or treatment of any one of embodiments 1 to 23, wherein, at the time of the first administration of the CDK4 / 6 inhibitor, the cancer has acquired resistance to one or more previously administered FGFR inhibitors.

[0569] 25. The composition, drug, or treatment of any one of embodiments 1 to 24, wherein the cancer has acquired a mutation at the time of the first administration of the CDK4 / 6 inhibitor, making the cancer susceptible to developing resistance to one or more FGFR inhibitors.

[0570] 26. A composition, drug, or treatment for reducing the development of acquired resistance to inhibitory effects of fibroblast growth factor receptor inhibitors in a host with non-small cell lung cancer exhibiting FGFR abnormalities, wherein the treatment comprises administering an effective amount of a short-acting CDK4 / 6 inhibitor to the host and administering an effective amount of a selective fibroblast growth factor receptor (FGFR) inhibitor to the host, wherein the CDK4 / 6 inhibitor is selected from compounds I-VI or pharmaceutically acceptable salts thereof.

[0571] 27. The composition, drug, or treatment described in embodiment 26, wherein the FGFR abnormality is the result of FGFR mutation, FGFR overexpression or amplification, or FGFR translocation or fusion.

[0572] 28. The composition, drug, or treatment of any one of embodiments 26 to 27, wherein the FGFR abnormality is FGFR overexpression or amplification.

[0573] 29. The composition, drug, or treatment of any one of embodiments 26 to 28, wherein the non-small cell lung cancer is large cell lung cancer.

[0574] 30. The composition, drug, or treatment of any one of embodiments 26 to 28, wherein the non-small cell lung cancer is squamous cell carcinoma.

[0575] 31. The composition, drug, or treatment of any one of embodiments 26 to 30, wherein the selective FGFR inhibitor is selected from the following: erdatinib, pemitinib, inflistatinib, AZD4547, fabatinib, deratinib, LY287445, Debio1347, PRN1371, alonib, bemarituzumab, and FIIN-2 or pharmaceutically acceptable salts thereof.

[0576] 32. The composition, drug, or treatment of any one of embodiments 26 to 31, wherein the CDK4 / 6 inhibitor is compound I, or a pharmaceutically acceptable salt thereof.

[0577] 33. The composition, medicine, or treatment of any one of embodiments 26 to 31, wherein the CDK4 / 6 inhibitor is compound IA.

[0578] 34. The composition, drug, or treatment of embodiment 33, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2°, and 22.4±0.2°.

[0579] 35. The composition, drug, or treatment of any one of embodiments 26 to 31, wherein the CDK4 / 6 inhibitor is compound III, or a pharmaceutically acceptable salt thereof.

[0580] 36. The composition, drug, or treatment of any one of embodiments 26 to 35, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 14 consecutive days or 21 consecutive days.

[0581] 37. The composition, drug, or treatment of any one of embodiments 26 to 35, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 28 consecutive days.

[0582] 38. The composition, drug, or treatment of any one of embodiments 26 to 35, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 35 consecutive days.

[0583] 39. The composition, drug, or treatment of any one of embodiments 26 to 35, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 56 consecutive days.

[0584] 40. The composition, medicine, or treatment of any one of embodiments 26 to 39, wherein the FGFR inhibitor is administered at least once daily for at least 14 consecutive days or 21 consecutive days.

[0585] 41. The composition, medicine, or treatment of any one of embodiments 26 to 39, wherein the FGFR inhibitor is administered at least once daily for at least 28 consecutive days.

[0586] 42. The composition, drug, or treatment of any one of embodiments 26 to 39, wherein the FGFR inhibitor is administered at least once daily for at least 35 consecutive days.

[0587] 43. The composition, drug, or treatment of any one of embodiments 26 to 39, wherein the FGFR inhibitor is administered at least once daily for at least 56 consecutive days.

[0588] 44. The composition, drug, or treatment of any one of embodiments 26 to 43, wherein the host has not been treated with the CDK4 / 6 inhibitor at the time of the first administration of the CDK4 / 6 inhibitor.

[0589] 45. The composition, drug, or treatment of any one of embodiments 26 to 44, wherein the cancer has acquired resistance to one or more previously administered FGFR inhibitors at the time of the first administration of the CDK4 / 6 inhibitor.

[0590] 46. ​​The composition, drug, or treatment of any one of embodiments 26 to 45, wherein the cancer has acquired a mutation at the time of the first administration of the CDK4 / 6 inhibitor, making the cancer susceptible to developing resistance to one or more FGFR inhibitors.

[0591] 47. A composition, drug, or treatment for treating a host with gastric adenocarcinoma having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by FGFR2 abnormalities, wherein the treatment comprises administering to the host an effective amount of a short-acting CDK4 / 6 inhibitor and administering to the host an effective amount of a selective fibroblast growth factor receptor (FGFR) inhibitor, wherein the CDK4 / 6 inhibitor is selected from compounds I-VI, or pharmaceutically acceptable salts thereof.

[0592] 48. The composition, drug, or treatment described in embodiment 47, wherein the FGFR2 abnormality is the result of FGFR2 mutation, FGFR2 overexpression or amplification, or FGFR2 translocation or fusion.

[0593] 49. The composition, drug, or treatment described in embodiment 47, wherein the FGFR2 abnormality is FGFR2 overexpression or amplification.

[0594] 50. The composition, drug, or treatment of any one of embodiments 47 to 49, wherein the selective FGFR inhibitor is selected from the following: erdatinib, pemitinib, inflistatinib, AZD4547, fabatinib, deratinib, LY287445, Debio1347, PRN1371, alonib, bemarituzumab, and FIIN-2 or pharmaceutically acceptable salts thereof.

[0595] 51. The composition, drug, or treatment of any one of embodiments 47 to 50, wherein the CDK4 / 6 inhibitor is compound I, or a pharmaceutically acceptable salt thereof.

[0596] 52. The composition, medicine, or treatment of any one of embodiments 47 to 50, wherein the CDK4 / 6 inhibitor is compound IA.

[0597] 53. The composition, drug, or treatment of embodiment 52, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2°, and 22.4±0.2°.

[0598] 54. The composition, drug, or treatment of any one of embodiments 47 to 50, wherein the CDK4 / 6 inhibitor is compound III, or a pharmaceutically acceptable salt thereof.

[0599] 55. The composition, drug, or treatment of any one of embodiments 47 to 54, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 14 consecutive days or 21 consecutive days.

[0600] 56. The composition, drug, or treatment of any one of embodiments 47 to 54, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 28 consecutive days.

[0601] 57. The composition, drug, or treatment of any one of embodiments 47 to 54, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 35 consecutive days.

[0602] 58. The composition, drug, or treatment of any one of embodiments 47 to 54, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 56 consecutive days.

[0603] 59. The composition, drug, or treatment of any one of embodiments 47 to 58, wherein the FGFR inhibitor is administered at least once daily for at least 14 consecutive days or 21 consecutive days.

[0604] 60. The composition, drug, or treatment of any one of embodiments 47 to 58, wherein the FGFR inhibitor is administered at least once daily for at least 28 consecutive days.

[0605] 61. The composition, medicine, or treatment of any one of embodiments 47 to 58, wherein the FGFR inhibitor is administered at least once daily for at least 35 consecutive days.

[0606] 62. The composition, drug, or treatment of any one of embodiments 47 to 58, wherein the FGFR inhibitor is administered at least once daily for at least 56 consecutive days.

[0607] 63. The composition, drug, or treatment of any one of embodiments 47 to 62, wherein the host has not been treated with the CDK4 / 6 inhibitor at the time of the first administration of the CDK4 / 6 inhibitor.

[0608] 64. The composition, drug, or treatment of any one of embodiments 47 to 63, wherein, at the time of the first administration of the CDK4 / 6 inhibitor, the cancer has acquired resistance to one or more previously administered FGFR inhibitors.

[0609] 65. The composition, drug, or treatment of any one of embodiments 47 to 64, wherein the cancer has acquired a mutation at the time of the first administration of the CDK4 / 6 inhibitor, making the cancer susceptible to developing resistance to one or more FGFR inhibitors.

[0610] 66. A composition, drug, or treatment for reducing the development of acquired resistance to inhibitory effects of fibroblast growth factor receptor inhibitors in a host with gastric adenocarcinoma exhibiting FGFR abnormalities, wherein the treatment comprises administering an effective amount of a short-acting CDK4 / 6 inhibitor to the host and administering an effective amount of a selective fibroblast growth factor receptor (FGFR) inhibitor to the host, wherein the CDK4 / 6 inhibitor is selected from compounds I-VI, or pharmaceutically acceptable salts thereof.

[0611] 67. The composition, drug, or treatment described in embodiment 66, wherein the FGFR abnormality is the result of FGFR mutation, FGFR overexpression or amplification, or FGFR translocation or fusion.

[0612] 68. The composition, drug, or treatment of any one of embodiments 66 to 67, wherein the FGFR abnormality is FGFR overexpression or amplification.

[0613] 69. The composition, drug, or treatment of any one of embodiments 66 to 68, wherein the selective FGFR inhibitor is selected from the following: erdatinib, pemitinib, inflistatinib, fabatinib, deratinib, LY287445, Debio1347, PRN1371, alonibuprofen, bemarituzumab, GSK3052230, and FIIN-2.

[0614] 70. The composition, drug, or treatment of any one of embodiments 66 to 69, wherein the CDK4 / 6 inhibitor is compound I, or a pharmaceutically acceptable salt thereof.

[0615] 71. The composition, medicine, or treatment of any one of embodiments 66 to 69, wherein the CDK4 / 6 inhibitor is compound IA.

[0616] 72. The composition, drug, or treatment of embodiment 71, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2°, and 22.4±0.2°.

[0617] 73. The composition, drug, or treatment of any one of embodiments 66 to 69, wherein the CDK4 / 6 inhibitor is compound III, or a pharmaceutically acceptable salt thereof.

[0618] 74. The composition, drug, or treatment of any one of embodiments 66 to 73, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 14 consecutive days or 21 consecutive days.

[0619] 75. The composition, drug, or treatment of any one of embodiments 66 to 73, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 28 consecutive days.

[0620] 76. The composition, drug, or treatment of any one of embodiments 66 to 73, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 35 consecutive days.

[0621] 77. The composition, drug, or treatment of any one of embodiments 66 to 73, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 56 consecutive days.

[0622] 78. The composition, drug, or treatment of any one of embodiments 66 to 77, wherein the FGFR inhibitor is administered at least once daily for at least 14 consecutive days or 21 consecutive days.

[0623] 79. The composition, drug, or treatment of any one of embodiments 66 to 77, wherein the FGFR inhibitor is administered at least once daily for at least 28 consecutive days.

[0624] 80. The composition, drug, or treatment of any one of embodiments 66 to 77, wherein the FGFR inhibitor is administered at least once daily for at least 35 consecutive days.

[0625] 81. The composition, drug, or treatment of any one of embodiments 66 to 77, wherein the FGFR inhibitor is administered at least once daily for at least 56 consecutive days.

[0626] 82. The composition, drug, or treatment of any one of embodiments 66 to 81, wherein the host has not been treated with the CDK4 / 6 inhibitor at the time of the first administration of the CDK4 / 6 inhibitor.

[0627] 83. The composition, drug, or treatment of any one of embodiments 66 to 82, wherein the cancer has acquired resistance to one or more previously administered FGFR inhibitors at the time of the first administration of the CDK4 / 6 inhibitor.

[0628] 84. The composition, drug, or treatment of any one of embodiments 66 to 83, wherein the cancer has acquired a mutation at the time of the first administration of the CDK4 / 6 inhibitor, making the cancer susceptible to developing resistance to one or more FGFR inhibitors.

[0629] 85. A composition, drug, or treatment for treating a host with dysregulated fibroblast growth factor receptor (FGFR) signaling caused by FGFR1 amplification, wherein the treatment comprises administering to the host an effective amount of a short-acting CDK4 / 6 inhibitor and administering to the host an effective amount of a selective fibroblast growth factor receptor (FGFR) inhibitor, wherein the CDK4 / 6 inhibitor is selected from compounds I-VI, or pharmaceutically acceptable salts thereof, and wherein the cancer is selected from non-small cell lung cancer, small cell lung cancer, triple-negative breast cancer, osteosarcoma, and HR+, HER2-amplified breast cancer, pilocytic astrocytoma, and glioblastoma.

[0630] 86. The composition, drug, or treatment according to any one of embodiments 85, wherein the selective FGFR inhibitor is selected from the following: erdatinib, pemitinib, inflistatinib, AZD4547, fabatinib, deratinib, Debio1347, PRN1371, FIIN2, GSK3052230, and PD173074.

[0631] 87. The composition, drug, or treatment of any one of embodiments 85 to 86, wherein the CDK4 / 6 inhibitor is compound I, or a pharmaceutically acceptable salt thereof.

[0632] 88. The composition, medicine, or treatment of any one of embodiments 85 to 86, wherein the CDK4 / 6 inhibitor is compound IA.

[0633] 89. The composition, drug, or treatment of embodiment 88, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2°, and 22.4±0.2°.

[0634] 90. The composition, drug, or treatment of any one of embodiments 85 to 86, wherein the CDK4 / 6 inhibitor is compound III, or a pharmaceutically acceptable salt thereof.

[0635] 91. The composition, drug, or treatment of any one of embodiments 85 to 90, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 21 consecutive days.

[0636] 92. The composition, drug, or treatment of any one of embodiments 85 to 90, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 28 consecutive days.

[0637] 93. The composition, drug, or treatment of any one of embodiments 85 to 90, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 35 consecutive days.

[0638] 94. The composition, drug, or treatment of any one of embodiments 85 to 90, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 56 consecutive days.

[0639] 95. The composition, drug, or treatment of any one of embodiments 85 to 94, wherein the FGFR inhibitor is administered at least once daily for at least 14 consecutive days or 21 consecutive days.

[0640] 96. The composition, drug, or treatment of any one of embodiments 85 to 94, wherein the FGFR inhibitor is administered at least once daily for at least 28 consecutive days.

[0641] 97. The composition, drug, or treatment of any one of embodiments 85 to 94, wherein the FGFR inhibitor is administered at least once daily for at least 35 consecutive days.

[0642] 98. The composition, drug, or treatment according to any one of embodiments 85 to 94, wherein the FGFR inhibitor is administered at least once daily for at least 56 consecutive days.

[0643] 99. The composition, drug, or treatment of any one of embodiments 85 to 98, wherein the host has not been treated with the CDK4 / 6 inhibitor at the time of the first administration of the CDK4 / 6 inhibitor.

[0644] 100. The composition, drug, or treatment of any one of embodiments 85 to 99, wherein, at the time of the first administration of the CDK4 / 6 inhibitor, the cancer has acquired resistance to one or more previously administered FGFR inhibitors.

[0645] 101. The composition, drug, or treatment of any one of embodiments 85 to 100, wherein the cancer has acquired a mutation at the time of the first administration of the CDK4 / 6 inhibitor, making the cancer susceptible to developing resistance to one or more FGFR inhibitors.

[0646] 102. A composition, drug, or treatment for treating a host with dysregulated fibroblast growth factor receptor (FGFR) signaling transduction caused by FGFR2 abnormalities, wherein the treatment comprises administering an effective amount of a short-acting CDK4 / 6 inhibitor to the host and administering an effective amount of a selective fibroblast growth factor receptor (FGFR) inhibitor to the host, wherein the CDK4 / 6 inhibitor is selected from compounds I-VI, or pharmaceutically acceptable salts thereof, and wherein the cancer is selected from ER+, HER2-amplified breast cancer, endometrial cancer, non-small cell lung cancer, gastric cancer, intrahepatic cholangiocarcinoma, and thyroid cancer.

[0647] 103. The composition, drug, or treatment of embodiment 102, wherein the FGFR2 abnormality is selected from the following: FGFR2 amplification, FGFR2 mutation, and FGFR2 translocation.

[0648] 104. The composition, drug, or treatment of any one of embodiments 102 to 103, wherein the selective FGFR2 inhibitor is selected from the following: erdatinib, pemitinib, inflistatinib, fabatinib, deratinib, LY287445, Debio1347, PRN1371, alonibuprofen, bemarituzumab, GSK3052230, and FIIN-2.

[0649] 105. The composition, drug, or treatment of any one of embodiments 102 to 104, wherein the CDK4 / 6 inhibitor is compound I, or a pharmaceutically acceptable salt thereof.

[0650] 106. The composition, medicine, or treatment of any one of embodiments 102 to 104, wherein the CDK4 / 6 inhibitor is compound IA.

[0651] 107. The composition, drug, or treatment of embodiment 106, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2°, and 22.4±0.2°.

[0652] 108. The composition, drug, or treatment of any one of embodiments 102 to 104, wherein the CDK4 / 6 inhibitor is compound III, or a pharmaceutically acceptable salt thereof.

[0653] 109. The composition, drug, or treatment of any one of embodiments 102 to 108, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 14 consecutive days or 21 consecutive days.

[0654] 110. The composition, drug, or treatment of any one of embodiments 102 to 108, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 28 consecutive days.

[0655] 111. The composition, drug, or treatment of any one of embodiments 102 to 108, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 35 consecutive days.

[0656] 112. The composition, drug, or treatment of any one of embodiments 102 to 108, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 56 consecutive days.

[0657] 113. The composition, drug, or treatment of any one of embodiments 102 to 112, wherein the FGFR inhibitor is administered at least once daily for at least 21 consecutive days.

[0658] 114. The composition, drug, or treatment of any one of embodiments 102 to 112, wherein the FGFR inhibitor is administered at least once daily for at least 28 consecutive days.

[0659] 115. The composition, drug, or treatment of any one of embodiments 102 to 112, wherein the FGFR inhibitor is administered at least once daily for at least 35 consecutive days.

[0660] 116. The composition, drug, or treatment of any one of embodiments 102 to 112, wherein the FGFR inhibitor is administered at least once daily for at least 56 consecutive days.

[0661] 117. The composition, drug, or treatment of any one of embodiments 102 to 116, wherein the host has not been treated with the CDK4 / 6 inhibitor at the time of the first administration of the CDK4 / 6 inhibitor.

[0662] 118. The composition, drug, or treatment of any one of embodiments 102 to 117, wherein, at the time of the first administration of the CDK4 / 6 inhibitor, the cancer has acquired resistance to one or more previously administered FGFR inhibitors.

[0663] 119. The composition, drug, or treatment of any one of embodiments 102 to 118, wherein the cancer has acquired a mutation at the time of the first administration of the CDK4 / 6 inhibitor, making the cancer susceptible to developing resistance to one or more FGFR inhibitors.

[0664] 120. A composition, drug, or treatment for treating a host with dysregulated fibroblast growth factor receptor (FGFR) signaling caused by FGFR3 abnormalities, wherein the treatment comprises administering to the host an effective amount of a short-acting CDK4 / 6 inhibitor and administering to the host an effective amount of a selective fibroblast growth factor receptor (FGFR) inhibitor, wherein the CDK4 / 6 inhibitor is selected from compounds I-VI, or pharmaceutically acceptable salts thereof, and wherein the cancer is selected from glioblastoma, non-small cell lung cancer, cervical cancer, and multiple myeloma.

[0665] 121. The composition, drug, or treatment of embodiment 120, wherein the FGFR3 abnormality is selected from the following: FGFR3 amplification, FGFR3 mutation, and FGFR3 translocation.

[0666] 122. The composition, drug, or treatment of any one of embodiments 120 to 121, wherein the selective FGFR inhibitor is selected from the following: erdatinib, pemitinib, inflistatinib, fabatinib, deratinib, LY287445, Debio1347, PRN1371, MGFR1877S, vorvastatinib, and FIIN-2.

[0667] 123. The composition, drug, or treatment of any one of embodiments 120 to 122, wherein the CDK4 / 6 inhibitor is compound I, or a pharmaceutically acceptable salt thereof.

[0668] 124. The composition, medicine, or treatment of any one of embodiments 120 to 122, wherein the CDK4 / 6 inhibitor is compound IA.

[0669] 125. The composition, drug, or treatment of embodiment 124, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2°, and 22.4±0.2°.

[0670] 126. The composition, drug, or treatment of any one of embodiments 120 to 125, wherein the CDK4 / 6 inhibitor is compound III, or a pharmaceutically acceptable salt thereof.

[0671] 127. The composition, drug, or treatment of any one of embodiments 120 to 126, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 14 consecutive days or 21 consecutive days.

[0672] 128. The composition, drug, or treatment of any one of embodiments 120 to 126, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 28 consecutive days.

[0673] 129. The composition, drug, or treatment of any one of embodiments 120 to 126, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 35 consecutive days.

[0674] 130. The composition, drug, or treatment of any one of embodiments 120 to 126, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 56 consecutive days.

[0675] 131. The composition, medicine, or treatment of any one of embodiments 120 to 130, wherein the FGFR inhibitor is administered at least once daily for at least 14 consecutive days or 21 consecutive days.

[0676] 132. The composition, medicine, or treatment of any one of embodiments 120 to 130, wherein the FGFR inhibitor is administered at least once daily for at least 28 consecutive days.

[0677] 133. The composition, medicine, or treatment of any one of embodiments 120 to 130, wherein the FGFR inhibitor is administered at least once daily for at least 35 consecutive days.

[0678] 134. The composition, medicine, or treatment of any one of embodiments 120 to 130, wherein the FGFR inhibitor is administered at least once daily for at least 56 consecutive days.

[0679] 135. The composition, drug, or treatment of any one of embodiments 120 to 134, wherein the host has not been treated with the CDK4 / 6 inhibitor at the time of the first administration of the CDK4 / 6 inhibitor.

[0680] 136. The composition, drug, or treatment of any one of embodiments 120 to 135, wherein the cancer has acquired resistance to one or more previously administered FGFR inhibitors at the time of the first administration of the CDK4 / 6 inhibitor.

[0681] 137. The composition, drug, or treatment of any one of embodiments 120 to 136, wherein the cancer has acquired a mutation at the time of the first administration of the CDK4 / 6 inhibitor, making the cancer susceptible to resistance to one or more FGFR inhibitors.

[0682] 138. A composition, drug, or treatment for treating a host with dysregulated fibroblast growth factor receptor (FGFR) signaling caused by FGFR4 or FGF abnormalities, wherein the treatment comprises administering to the host an effective amount of a short-acting CDK4 / 6 inhibitor and administering to the host an effective amount of a selective fibroblast growth factor receptor (FGFR) inhibitor, wherein the CDK4 / 6 inhibitor is compound I-VI, or a pharmaceutically acceptable salt thereof, and wherein the cancer is selected from hepatocellular carcinoma, rhabdomyosarcoma, endometrial cancer, ER+, HER2-amplified breast cancer, and ovarian cancer.

[0683] 139. The composition, drug, or treatment of embodiment 138, wherein the FGFR4 abnormality is selected from the following: FGFR4 amplification, FGFR4 mutation, and FGFR4 translocation.

[0684] 140. The composition, drug, or treatment of any one of embodiments 138 to 139, wherein the selective FGFR inhibitor is selected from the following: infelterinib, fubatinib, deratinib, LY287445, INCB062079, BLU9931, H3-6527, fexotinib, robrutinib, Debio1347, PRN1371, and FIIN-2.

[0685] 141. The composition, medicine, or treatment of any one of embodiments 138 to 140, wherein the CDK4 / 6 inhibitor is compound I, or a pharmaceutically acceptable salt thereof.

[0686] 142. The composition, medicine, or treatment of any one of embodiments 138 to 140, wherein the CDK4 / 6 inhibitor is compound IA.

[0687] 143. The composition, drug, or treatment of embodiment 142, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2°, and 22.4±0.2°.

[0688] 144. The composition, drug, or treatment of any one of embodiments 138 to 143, wherein the CDK4 / 6 inhibitor is compound III, or a pharmaceutically acceptable salt thereof.

[0689] 145. The composition, drug, or treatment of any one of embodiments 138 to 144, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 14 consecutive days or 21 consecutive days.

[0690] 146. The composition, drug, or treatment of any one of embodiments 138 to 144, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 28 consecutive days.

[0691] 147. The composition, drug, or treatment of any one of embodiments 138 to 144, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 35 consecutive days.

[0692] 148. The composition, drug, or treatment of any one of embodiments 138 to 144, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 56 consecutive days.

[0693] 149. The composition, medicine, or treatment of any one of embodiments 138 to 148, wherein the FGFR inhibitor is administered at least once daily for at least 14 consecutive days or 21 consecutive days.

[0694] 150. The composition, medicine, or treatment of any one of embodiments 138 to 148, wherein the FGFR inhibitor is administered at least once daily for at least 28 consecutive days.

[0695] 151. The composition, drug, or treatment of any one of embodiments 138 to 148, wherein the FGFR inhibitor is administered at least once daily for at least 35 consecutive days.

[0696] 152. The composition, drug, or treatment of any one of embodiments 138 to 151, wherein the FGFR inhibitor is administered at least once daily for at least 56 consecutive days.

[0697] 153. The composition, drug, or treatment of any one of embodiments 138 to 152, wherein the host has not been treated with the CDK4 / 6 inhibitor at the time of the first administration of the CDK4 / 6 inhibitor.

[0698] 154. The composition, drug, or treatment of any one of embodiments 138 to 153, wherein, at the time of the first administration of the CDK4 / 6 inhibitor, the cancer has acquired resistance to one or more previously administered FGFR inhibitors.

[0699] 155. The composition, drug, or treatment of any one of embodiments 138 to 154, wherein the cancer has acquired a mutation that makes the cancer susceptible to resistance to one or more FGFR inhibitors at the time of the first administration of the CDK4 / 6 inhibitor.

[0700] 156. The composition, drug, or treatment of any one of embodiments 1 to 151, wherein the cancer is metastatic.

[0701] 157. The composition, drug, or treatment of any one of embodiments 1 to 156, wherein the cancer to be treated does not have mutations mutually exclusive with FGFR abnormalities, such as KRAS or BRAF mutations.

[0702] 158. The composition, drug, or treatment of any one of embodiments 1 to 157, wherein the cancer progresses during or after at least one prior chemotherapy, such as platinum-based chemotherapy, such as cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatinum tetranitrate, phenanthreneplatin, pyridineplatin, or saxaplatin.

[0703] 159. The composition, drug, or treatment of any one of embodiments 1 to 157, wherein the host is a human.

[0704] 160. A composition, drug, or treatment for treating a host with cancer having a dysregulated fibroblast growth factor receptor (FGFR) signaling pathway caused by FGFR or FGF abnormalities, wherein the treatment comprises administering to the host an effective amount of a short-acting CDK4 / 6 inhibitor and administering to the host an effective amount of a selective fibroblast growth factor receptor (FGFR) inhibitor, wherein the CDK4 / 6 inhibitor is selected from compounds I-VI or pharmaceutically acceptable salts thereof.

[0705] 161. The composition, drug, or treatment described in embodiment 160, wherein the FGFR or FGF abnormality is the result of mutation, overexpression, amplification, translocation, or fusion.

[0706] 162. The composition, drug, or treatment of any one of embodiments 160 to 162, wherein the selective FGFR inhibitor is selected from the following: erdatinib, infelterinib, pemitinib, AZD4547, fabatinib (TAS-120), deratinib, robrutinib, LY287445, INCB062079, BLU9931, PRN1371, FIIN-2, PD173074, H3B-6527, fexotinib, alonibub, bemarituzumab, vorvastatinab, MGFR1877S, and Debio1347, or pharmaceutically acceptable salts thereof.

[0707] 163. The composition, drug, or treatment of any one of embodiments 160 to 162, wherein the CDK4 / 6 inhibitor is compound I, or a pharmaceutically acceptable salt thereof.

[0708] 164. The composition, medicine, or treatment of any one of embodiments 160 to 162, wherein the CDK4 / 6 inhibitor is compound IA.

[0709] 165. The composition, drug, or treatment of embodiment 164, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2°, and 22.4±0.2°.

[0710] 166. The composition, drug, or treatment of any one of embodiments 160 to 165, wherein the CDK4 / 6 inhibitor is compound III, or a pharmaceutically acceptable salt thereof.

[0711] 167. The composition, drug, or treatment of any one of embodiments 160 to 166, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 14 consecutive days or 21 consecutive days.

[0712] 168. The composition, drug, or treatment of any one of embodiments 160 to 166, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 28 consecutive days.

[0713] 169. The composition, drug, or treatment of any one of embodiments 160 to 166, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 35 consecutive days.

[0714] 170. The composition, drug, or treatment of any one of embodiments 160 to 166, wherein the CDK4 / 6 inhibitor is administered to the host at least once daily for at least 56 consecutive days.

[0715] 171. The composition, drug, or treatment of any one of embodiments 160 to 170, wherein the FGFR inhibitor is administered at least once daily for at least 14 consecutive days or 21 consecutive days.

[0716] 172. The composition, drug, or treatment of any one of embodiments 160 to 170, wherein the FGFR inhibitor is administered at least once daily for at least 28 consecutive days.

[0717] 173. The composition, drug, or treatment of any one of embodiments 160 to 170, wherein the FGFR inhibitor is administered at least once daily for at least 35 consecutive days.

[0718] 174. The composition, drug, or treatment of any one of embodiments 160 to 170, wherein the FGFR inhibitor is administered at least once daily for at least 56 consecutive days.

[0719] 175. The composition, drug, or treatment of any one of embodiments 160 to 174, wherein the host has not been treated with the CDK4 / 6 inhibitor at the time of the first administration of the CDK4 / 6 inhibitor.

[0720] 176. The composition, drug, or treatment of any one of embodiments 160 to 175, wherein, at the time of the first administration of the CDK4 / 6 inhibitor, the cancer has acquired resistance to one or more previously administered FGFR inhibitors.

[0721] 177. The composition, drug, or treatment of any one of embodiments 160 to 176, wherein the cancer has acquired a mutation that makes the cancer susceptible to resistance to one or more FGFR inhibitors at the time of the first administration of the CDK4 / 6 inhibitor.

[0722] 178. The composition, drug, or treatment of any one of embodiments 160 to 177, wherein other anticancer agents are administered to the host.

[0723] 179. The composition, drug, or treatment described in embodiment 178, wherein the other anticancer agent is a checkpoint inhibitor, PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, T cell-activated V domain Ig repressor (VISTA) inhibitor, or other inhibitor.

[0724] 180. The composition, drug, or treatment of any one of embodiments 1 to 179, wherein the cancer is CDK4 / 6 replication dependent.

[0725] Examples

[0726] Example 1: Cell proliferation and viability assay

[0727] use Luminescent cell viability assay determined cell viability. This assay was performed in three separate FGFR-mutant cell lines using a single agent (erdatinib or lerociclib) or pairs of targeted agents (erdatinib + lerociclib or erdatinib + palbociclib): H1581 (FGFR1-amplified NSCLC large cell carcinoma), Snu-16 (FGFR2-amplified gastric adenocarcinoma), and RT4 (FGFR3m bladder cancer - FGFR3–TACC3 fusion). In short, 1 x 10⁻⁶ cells were used. 3 Cells were seeded into 96-well plates and allowed to adhere overnight. The next day, cells were treated with a single or dual agent (using an equimolar ratio). After 120–144 hours, 0.1 mg / mL resazurin (Sigma Aldrich) or 20% of the manufacturer's recommended volume of Cell Titer Glo (Promega) was added. The optical density (OD) of each well was measured at 562 nm (reference wavelength: 650 nm) using a SpectraMax 250 (Molecular Devices) or EnVision (Perkin Elmer) microplate reader. The half-maximum inhibitory concentration (IC50) was calculated using nonlinear regression and sigmoid dose-response curves with GraphPad Prism4 software. Viability is expressed as a percentage of untreated controls. Results for H1581 (FGFR1m NSCLC) cells are shown below. Figure 1A As shown. Results for Snu-16 (FGFR2m gastric cancer) cells are as follows. Figure 1B As shown. Results for RT4 (FGFR3m bladder cancer) cells are as follows. Figure 1C As shown, the results indicate that the combination of lerociclib (compound I) and erdatinib consistently and synergistically inhibits FGFR mutant cell lines compared to either compound alone. Furthermore, at lower concentrations, lerociclib and erdatinib were shown to be more effective than the combination of erdatinib and palbociclib (another selective CDK4 / 6 inhibitor), for example, in FGFR2m gastric cancer cell lines and FGFR3m bladder cancer cell lines.

[0728] Example 2: Measuring the effects of lerociclib and erdatinib on acquired resistance

[0729] For colony formation assays, RT4 (FGFR3m bladder cancer) cells were seeded at a density of 10,000 cells / well in 6-well plates containing 10% (v / v) fetal bovine serum. The assay was performed using a single agent (erdatinib or lerociclib) or a combination of erdatinib (100 nM) and lerociclib (300 nM). After treatment, the plates were pulled and the cells stained with crystal violet (Merck Millipore, Darmstadt, Germany). The optical density (OD) of each well was measured at 562 nm (reference wavelength: 650 nm) using a SpectraMax 250 (Molecular Devices) or EnVision (Perkin Elmer) microplate reader. Growth was measured using GraphPad Prism4 software. Results are as follows: Figure 2 Definitions As shown in the figure, the addition of lerociclib (compound I) significantly improved cell sensitivity over time compared to erdatinib treatment alone, indicating inhibition of the development of FGFR inhibitor resistance in FGFRm cell lines.

[0730] Example 3: Compound 1 was converted into its HCl counterpart, namely compound 1A.

[0731] A representative synthesis of compound 1A is provided:

[0732]

[0733] Compound 1 (0.9 kg, 1.9 mol, 1 equivalent) was charged into a 22 L flask and dissolved in 3.78 L of 2 M hydrochloric acid aqueous solution. The solution was heated to 50 ± 5 °C and stirred for 30 min. The resulting mixture was filtered through diatomaceous earth (or the solution could be filtered through a 0.45 μm in-line filter) to give compound 1A. The flask was rinsed with 0.1 M hydrochloric acid solution to collect any excess compound 1A. Compound 1A was then heated to 50 ± 5 °C while acetone (6.44 L) was slowly added. The solution was stirred at 50 ± 5 °C for 30 min, then cooled to 20 ± 5 °C and stirred for another 2 h. The solid was collected by filtration, washed with acetone, and dried to give 820.90 g of compound 1A (yield 82.1%). In some embodiments, ethanol was used instead of acetone.

[0734] Example 4: Recrystallization procedure for producing type B from compound 1

[0735] Recrystallization Method 1: Compound 1 is placed in a suitably sized flask or reactor, dissolved in an aqueous hydrochloric acid solution, and heated to at least 55 ± 10 °C. The solution is stirred for about 45 minutes, and the resulting mixture is filtered through an inline filter. Acetone is added at 55 ± 10 °C for one hour, and the solution is stirred for another hour. The temperature is lowered to about 25 ± 5 °C, and the solution is stirred for at least 2 hours. The solid is collected by filtration, washed with acetone, and dried to give compound 1A, type B.

[0736] Example 5: XRPD analysis of crystal form B of compound 1A

[0737] Type B XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer, which uses a copper radiation incident beam generated using an Optix long narrow focusing source. An elliptical graded multilayer mirror was used to focus the Cu Kα X-rays through the sample and onto the detector. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to verify that the observed Si 111 peak position was consistent with the NIST-certified position. The sample was clamped between 3 μm thick films and analyzed in transmission geometry. A beam blocker, short antiscattering extension, and antiscattering blade were used to minimize background from air. Soller slits for both the incident and diffracted beams were used to minimize broadening caused by axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) at a distance of 240 mm from the sample and Data Collector software v.2.2b. Data acquisition parameters for each pattern are shown above the images in the data section of this report, including the divergence slit (DS) in front of the mirror.

[0738] Figure 7 shows the XRPD pattern of pure type B along with the indexing solution. The pure type B XRPD pattern exhibits sharp peaks, indicating that the sample is composed of crystalline material. The allowed peak positions in the XRPD indexing solution are 6.5, 8.1, 9.4, 9.6, 10.2, 10.6, 11.2, 12.2, 12.9, 13.0, 13.3, 13.4, 14.0, 14.4, 14.6, 15.0, 15.9, 16.2, 16.4, 16.5, 16.8, 18.1, 18.4, 18.5, 18.6, 18.6, 18.9, 19.1, 19.2, 19. .3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.4, 20.6, 21.3, 21.4, 21.8, 22.0, 22.2, 22.3, 22.4, 22.5, 22.8, 23.0, 23.1, 23.4, 23.8, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 25.4, 25.6, 25.7, 25.9, 2 6.0, 26.1, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.2, 27.3, 27.5, 27.6, 27.7, 27.9, 28.3, 28.4, 28.5, 28.7, 28.9, 29.0, 29.1, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30.0, 30.3, 30.4 30.5, 30.6, 30.7, 30.9, 31.2, 31.5, 31.6, 31.7, 31.8, 31.9, 32.0, 32.2, 32.3, 32.4, 32.5, 32.6, 32.7, 32.8, 33.1, 33.2, 33.3, 33.6, 33.7, 33.8, 34.0, 34.1, 34.2, 34.3, 34.6, 34.7, 34.8, 35.0 35.2, 35.3, 35.5, 35.6, 35.9, 36.0, 36.2, 36.5, 36.6, 36.7, 36.8, 36.9, 37.1, 37.2, 37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9 and 40.0°2θ.

[0739] For example, type B XRPDs can be indexed as follows: 6.47, 8.08, 9.42, 9.59, 10.18, 10.62, 11.22, 12.17, 12.91, 12.97, 13.27, 13.37, 14.03, 14.37, 14.63, 15.02, 15.93, 16.20, 16.35, 16.43, 16.47, 16.81, 18.10, 18.35, 18.41, 18.50, 18.55, 18.6,0 18.91, 19.11, 19.15, 19.24, 19.34, 19.43, 19.51, 19.61, 19.65, 19.76, 19.85, 19.90, 20.44, 20.61, 21.34, 21.43, 21.84, 21.95, 22.17, 22.28, 22.30, 22.33, 22.44, 22.54, 22.76, 22.81, 22.97, 23.00, 23.11, 23.42, 23.80, 24.11, 24.22, 24.34, 24.38, 24.40 24.48, 24.56, 24.57, 25.40, 25.56, 25.57, 25.59, 25.72, 25.74, 25.94, 25.99, 26.11, 26.28, 26.29, 26.37, 26.51, 26.58, 26.61, 26.73, 26.81, 26.92, 27.15, 27.19, 27.23, 27.31, 27.49, 27.57, 27.61, 27.71, 27.88, 27.94, 28.27, 28.41, 28.53, 28.71, 28.74 28.86, 28.94, 28.98, 29.03, 29.06, 29.08, 29.25, 29.30, 29.38, 29.51, 29.57, 29.61, 29.70, 29.73, 29.75, 29.90, 29.95, 30.31, 30.38, 30.42, 30.54, 30.55, 30.66, 30.73, 30.85, 30.87, 30.89, 31.23, 31.51, 31.55, 31.61, 31.70, 3 1.76, 31.77, 31.80, 31.81, 31.82, 31.82, 31.90, 31.91, 31.95, 32.17, 32.21, 32.23, 32.25, 32.36, 32.37, 32.43, 32.53, 32.54, 32.56, 32.61, 32.73, 32.80, 32.82, 33.05, 33.13, 33.17, 33.22, 33.28, 33.30, 33.60, 33.65, 33.71, 33.76, 33.77, 33.99, 34.01, 34.01, 34.05, 34.10, 34.17, 34.29, 34.55, 34.60, 34.62, 34.63, 34.68, 34.75, 34.76, 35.03, 35.16, 35.19, 35.21, 35.25, 35.31, 35.46, 35.61, 35.63, 35.85, 35 .86, 35.90, 35.97, 36.19, 36.45, 36.56, 36.58, 36.67, 36.68, 36.70, 36.71, 36.77, 36.85, 36.87, 36.90, 37.09, 37.19, 37.27, 37.28, 37.29, 37.32, 37.33, 37.37, 37.38, 37.48, 37.48, 37 .50, 37.51, 37.54, 37.61, 37.64, 37.65, 37.68, 37.69, 37.71, 37.74, 37.74, 37.76, 37.81, 37.83, 37.93, 37.94, 38.15, 38.19, 38.32, 38.36, 38.39, 38.46, 38.59, 38.63, 38.69, 38.76, 3 8.79, 38.85, 38.87, 38.88, 38.96, 38.98, 39.02, 39.05, 39.19, 39.27, 39.33, 39.36, 39.39, 39.43, 39.44, 39.53, 39.53, 39.6, 39.61, 39.70, 39.71, 39.72, 39.82, 39.87, 39.9, and 39.98°2θ.

[0740] The peaks observed in type B include 9.5±0.2, 18.1±0.2, 19.3±0.2, 22.4±0.2, 26.6±0.2 and 27.7±0.2°2θ.

[0741] The consistency between the allowed peak positions (marked with bars) and the observed peaks indicates consistent unit cell determination. Successful indexing of the pattern indicates that the sample is primarily composed of a single-crystal phase. The space groups consistent with the specified extinction symbols, unit cell parameters, and derived quantities are given in Table 8.

[0742] Table 8: XRPD parameters of compounds 1A and 1B

[0743]

[0744] In some embodiments, Type B is characterized in that the XRPD pattern includes at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2°, and 22.4±0.2°. In some embodiments, Type B is characterized in that the XRPD pattern includes at least three 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2°, and 22.4±0.2°. In some embodiments, Type B is characterized in that the XRPD pattern includes at least four 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2°, and 22.4±0.2°. In some embodiments, Type B is characterized in that the XRPD pattern includes at least five 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2°, and 22.4±0.2°. In some embodiments, Type B is characterized in that the XRPD pattern includes at least six 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2°, and 22.4±0.2°. In some embodiments, Type B is characterized in that the XRPD pattern includes 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2°, and 22.4±0.2°. In some embodiments, Type B is characterized in that the XRPD pattern includes at least a 2θ value of 9.5±0.4°.

[0745] This specification has been described with reference to embodiments of the invention. However, those skilled in the art will understand that various modifications and changes can be made without departing from the scope of the invention as set forth in the following claims. Accordingly, this specification should be considered illustrative rather than restrictive, and all such modifications are intended to be included within the scope of the invention.

Claims

1. Short-acting CDK4 / 6 inhibitor compounds with the following structures: The use of a pharmaceutically acceptable salt thereof in combination with a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) in the preparation of a medicament for treating a human host with cancer having dysregulation of the fibroblast growth factor receptor (FGFR) signaling pathway caused by an FGFR1 abnormality, wherein the FGFR1 abnormality is selected from the following: FGFR1 amplification, FGFR1 overexpression, FGFR1 mutation, FGFR1 translocation, and FGFR1 fusion.

2. The use according to claim 1, wherein the FGFR1 abnormality is FGFR1 overexpression or FGFR1 amplification.

3. The use according to claim 1, wherein the selective FGFR-TKI is selected from the following: erdatinib, pemitinib, inflistatinib, fabatinib, deratinib, Debio1347, PRN1371, FIIN-2, GSK3052230 and PD173074.

4. The use according to claim 1, wherein the CDK4 / 6 inhibitor is 5. The use according to claim 1, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2° and 22.4±0.2°.

6. The use according to claim 1, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the human host at least once daily for at least 28 consecutive days.

7. The use according to claim 1, wherein the human host has not experienced CDK4 / 6 inhibitor treatment at the time of the first administration of the CDK4 / 6 inhibitor.

8. The use according to claim 1, wherein the cancer has acquired resistance to one or more previously administered FGFR-TKIs at the time of the first administration of the CDK4 / 6 inhibitor.

9. The use according to claim 1, wherein the cancer has acquired a mutation at the time of the first administration of the CDK4 / 6 inhibitor, making the cancer susceptible to developing resistance to one or more FGFR-TKIs.

10. Short-acting CDK4 / 6 inhibitor compounds with the following structures: The use of a pharmaceutically acceptable salt thereof in combination with a selective fibroblast growth factor receptor-tyrosine kinase inhibitor (FGFR-TKI) in the preparation of a medicament for treating a human host with cancer having dysregulation of the fibroblast growth factor receptor (FGFR) signaling pathway caused by an FGFR2 abnormality, wherein the FGFR2 abnormality is selected from the following: FGFR2 amplification, FGFR2 overexpression, FGFR2 mutation, FGFR2 translocation, and FGFR2 fusion.

11. The use of claim 10, wherein the FGFR2 abnormality is FGFR2 amplification or FGFR2 overexpression.

12. The use as claimed in claim 10, wherein the selective FGFR-TKI is selected from the following: erdatinib, pemitinib, inflistatinib, fabatinib, deratinib, LY287445, Debio1347, PRN1371, alonib, bemarituzumab, and FIIN-2.

13. The use according to claim 10, wherein the CDK4 / 6 inhibitor is 14. The use according to claim 10, wherein the CDK4 / 6 inhibitor is compound IA, type B, wherein type B is characterized in that the XRPD pattern comprises at least two 2θ values ​​selected from the following: 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.9±0.2° and 22.4±0.2°.

15. The use according to claim 10, wherein the CDK4 / 6 inhibitor and the FGFR-TKI are administered to the human host at least once daily for at least 28 consecutive days.

16. The use according to claim 10, wherein the human host has not experienced CDK4 / 6 inhibitor treatment at the time of the first administration of the CDK4 / 6 inhibitor.

17. The use according to claim 10, wherein the cancer has acquired resistance to one or more previously administered FGFR-TKIs at the time of the first administration of the CDK4 / 6 inhibitor.

18. The use according to claim 10, wherein the cancer has acquired a mutation at the time of the first administration of the CDK4 / 6 inhibitor, making the cancer susceptible to developing resistance to one or more FGFR-TKIs.

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