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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Developed by G1 Therapeutics Inc. and designated by the FDA as a “breakthrough therapy”, trilaciclib (GIT-28) (Figure 6.78) is an experimental intravenously administered CDK4/6 inhibitor designed to reduce myelosuppression and preserve immune system function during chemotherapy. In preclinical studies it has been shown to produce transient G1 cell-cycle arrest, rendering hematopoietic stem and progenitor cells (HSPCs) resistant to chemotherapy-based cytotoxicity, thus allowing faster hematopoietic recovery, preservation of long-term function, and enhancement of antitumor immunity and activity. Structure of trilaciclib (GIT-28).
Thromboembolism profiles associated with cyclin-dependent kinase 4/6 inhibitors: a real-world pharmacovigilance study and a systematic review
Published in Expert Opinion on Drug Safety, 2023
Siyuan Gao, Yu Li, Zhichao He, Jianhong Zhu, Dan Liang, Shan Yang, Jiayao Mo, Kakei Lam, Xiaoxia Yu, Ming Huang, Junyan Wu
First, we found that all CDK4/6i increased the risk of VTE in the pharmacovigilance analysis, and these results remained stable under sensitivity analysis in the restricted tumor population. In addition, CDK4/6i-associated PE, DVT, thrombophlebitis, and portal vein thrombosis showed higher reported signals (Figure 1). PE and DVT, in particular, were reported at high rates (24.58% and 9.40%), and these thromboembolic diseases require our extensive attention. However, ribociclib showed a VTE incidence of less than 1% in the intervention group of RCT, with no significant difference compared to the control group. Therefore, we conservatively interpreted the risk of VTE in ribociclib, for which no significant risk differences were observed in the RCTs despite its strong signal of VTE in real-world data. There is a lack of evidence revealing the risk of thromboembolism associated with trilaciclib. However, our study showed a strong signal for trilaciclib in pharmacovigilance analysis and a high incidence of VTE (8%) in RCTs. Thus, more clinical attention is required for the VTE events related to trilaciclib.
Efficacy and Safety of CDK4/6 Inhibitors Combined with Endocrine Therapy in HR+/HER-2− ABC Patients: A Systematic Review and Meta-Analysis
Published in Cancer Investigation, 2021
Yongyan Li, Li Li, Qi Du, Yongfu Li, Haifang Yang, Qin Li
At present, the US Food and Drug Administration (FDA) has approved four cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors for medical use in the United States. Palbociclib, ribociclib, and abemaciclib were approved to be combined with endocrine drugs for clinical treatment of HR+/HER-2− ABC patients. Trilaciclib was approved for bone marrow protection in patients undergoing chemotherapy of small cell lung cancer. Palbociclib has been approved for first- and second-line treatment of HR+/HER-2− ABC patients. Ribociclib and abemaciclib have been approved for first- and back-line treatment of HR+/HER-2− ABC patients (9,10). CDK4/6 inhibitors combined with endocrine drugs can increase the treatment response rate and prolong disease control time in HR+/HER-2− ABC patients (11). Moreover, CDK4/6 inhibitors are oral agents that are more tolerable by patients than traditional intravenous chemotherapeutic agents. CDK4/6 inhibitors combined with endocrine drugs can improve clinical outcomes; however, this approach may increase the incidence of adverse events (AEs) and the financial burden on patients. Therefore, this study systematically evaluated the efficacy and safety of CDK4/6 inhibitors combined with ET and endocrine monotherapy for HR+/HER-2− ABC patients to provide accurate evidence for clinical application.
Cyclin-dependent kinase 4/6 inhibitors for cancer therapy: a patent review (2015 – 2019)
Published in Expert Opinion on Therapeutic Patents, 2020
Peng-Fei Wang, Han-Yue Qiu, Yun He, Hai-Liang Zhu
Trilaciclib (G1T28) is a newly developed CDK4/6-selective inhibitor with a tricyclic lactam core (Figure 1) and has been intensively investigated in recent years by G1 Therapeutics Inc [34]. A serial of pre-clinical trials on trilaciclib has been conducted and exhibited interesting pharmacological efficiency. Instead of being utilized as a stand-alone agent that exerting anti-proliferation activity, trilaciclib is used to reduce myelosuppression induced by chemotherapy in triple-negative breast cancer and small cell lung cancer. Other studies also indicate trilaciclib enhances the efficacy of combination chemotherapy plus distinct agents. Several randomized phase II clinical trials have already been initiated, and partly accomplished tests supported the intention of improving overall survival in patients with metastatic triple-negative breast cancer or small cell lung cancer [35–37]. The underlying biological mechanism for so lies in that the proliferation of bone marrow hematopoietic stem and progenitor cells (HSPC) is highly CDK 4/6-dependent [38]. When caused cell cycle arrested by CDKIs, these cells are less sensitive to chemotherapy agents and hence protected. Likewise, palbociclib has been observed to similarly increase lymphocytes, myeloid cells, platelet counts, and hematocrit levels when co-administrated with carboplatin than administrating carboplatin alone. Yet it has a long half-life of 25.9 h and is orally administered, making it unsuitable for shorter-acting intravenous chemotherapy, compared to trilaciclib with a half-life of 5 h and intravenous administration [39].