Abstract

Trilaciclib, a novel cyclin-dependent kinase 4/6 inhibitor, has demonstrated the ability to protect bone marrow from chemotherapy toxicity, improving patients' quality of life (QoL). This review describes the mechanism of action, efficacy, and toxicity profile of trilaciclib. Trilaciclib halts retinoblastoma protein phosphorylation during the early G1 phase, preventing the transition from the G1/S phase and inducing the cell cycle arrest in the G1 phase, which protects the hematopoietic cell lineages. Trilaciclib is indicated by the United States Food and Drug Administration and National Comprehensive Cancer Network to decrease the incidence of chemotherapy-induced myelosuppression in adult patients before a platinum/etoposide or topotecan containing regimen for extensive stage small cell lung cancer. Its ease of administration as an intravenous infusion, given before starting chemotherapy, and the favorable side effect profile make it a better-tolerated drug, improving patient QoL.

Introduction

Myelosuppressive chemotherapeutic agents have an associated risk of chemotherapy-induced myelosuppression (CIM). Neutropenic complications include febrile neutropenia, prolonged hospitalization days, and increased mortality rates.[1] Granulocyte colony-stimulating factor (G-CSF) reduces these side effects and improves patient outcomes.[2] However, financial burden, side effects of G-CSF, including bone pain, administration after chemotherapy mostly in a home-based setting, multiple uses of injections, and continued vulnerability to infection after chemotherapy remain unmet needs.[3] [4] [5] It is challenging to ensure the cold chain maintenance for the G-CSF injection and patient compliance in home-based settings, especially in the illiterate population. Trilaciclib, a novel cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, has shown promise in achieving this balance. Its ease of administration as an intravenous injection given just before chemotherapy addresses the logistic issues associated with traditional G-CSF injections.

This review delves into trilaciclib's mechanism of action, preclinical and clinical studies, safety profile, and potential applications. By preserving bone marrow and immune cells during chemotherapy, trilaciclib minimizes myelosuppression impact and promotes a more efficient approach to treatment.

Discovery, Mechanism of Action, Pharmacokinetics, Indications, and Contraindications

Trilaciclib's development stemmed from advancements in understanding the role of CDK4/6 in cell cycle regulation and the need for improved strategies to protect patients from chemotherapy's myelosuppressive effects. G1 therapeutics spearheaded the drug's research and conducted a series of pivotal trials. This led to its emergence as a promising myelopreservation agent in cancer therapy.

Trilaciclib (G1T28) selectively inhibits CDK4/6, crucial cell cycle regulators. This action halts retinoblastoma protein phosphorylation during the early G1 phase, preventing transition from the G1/S phase and inducing cell cycle arrest in the G1 phase. This protects the hematopoietic cell lineages (red blood cells [RBCs], platelets, neutrophils, and lymphocytes) from the cytotoxic effects of chemotherapy. Additionally, trilaciclib triggers apoptosis and inhibits the proliferation of tumor cells overexpressing CDK4/6. Moreover, for patients with CDK4/6-independent tumor cells, the drug protects against CIM. This safeguarding mechanism reduces myelosuppression and heightens immune responses during cancer treatment.[6]

Trilaciclib has an average terminal half-life of approximately 14 hours, primarily eliminated through the fecal route, with a minor contribution via the renal route. No dose adjustments are required according to differences in age, sex, or hepatic or renal function.

Trilaciclib is indicated by the United States Food and Drug Administration to decrease the incidence of CIM in adult patients before a platinum/etoposide or topotecan-containing regimen for extensive stage small cell lung cancer (ES-SCLC). National Comprehensive Cancer Network recommends trilaciclib as an option for decreasing the incidence of CIM in ES-SCLC. It is contraindicated in patients with a history of severe hypersensitivity to the drug. Ongoing research aims to explore its application in various cancer types and treatment regimens. Additionally, investigations are underway to evaluate its use in hematopoietic stem cell transplantation and radiation therapy.

Pivotal Trials

The pre-existing data for Trilaciclib and the various ongoing trials are provided in [Table 1] and [Table 2]. Trilaciclib has been shown to have benefits beyond preventing neutropenia and protecting other hematopoietic lineages such as RBCs and platelets. Trilaciclib can reduce the incidence of grade 4 neutropenia, grade ¾ anemia, thrombocytopenia, RBC transfusions, and erythropoiesis-stimulating agent administration. Additionally, trilaciclib has been shown to improve the quality of life (QoL). However, it is essential to note that these benefits may be tumor or chemotherapy-specific.[7] [8]

Dosage and Administration

The recommended dose of trilaciclib is 240 mg/m2 per dose. It is administered as a 30-minute intravenous infusion. It should be given 4 hours before starting chemotherapy. At most, the interval between two consecutive day doses should be 28 hours.

1.  Lyman GH. Febrile neutropenia: an ounce of prevention or a pound of cure. J Oncol Pract 2019; 15 (01) 27-29
   Crossref PubMed Google Scholar
2.  Crawford J, Ozer H, Stoller R. et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 1991; 325 (03) 164-170
   Crossref PubMed Google Scholar
3.  Crawford J, Dale DC, Kuderer NM. et al. Risk and timing of neutropenic events in adult cancer patients receiving chemotherapy: the results of a prospective nationwide study of oncology practice. J Natl Compr Canc Netw 2008; 6 (02) 109-118
   Crossref PubMed Google Scholar
4.  Dinan MA, Hirsch BR, Lyman GH. Management of chemotherapy-induced neutropenia: measuring quality, cost, and value. J Natl Compr Canc Netw 2015; 13 (01) e1-e7
   Crossref PubMed Google Scholar
5.  Kubista E, Glaspy J, Ann Holmes F. et al Bone Pain Associated with Once-Per-Cycle Pegfilgrastim Is Similar to Daily Filgrastim in Patients with Breast Cancer. Clin Breast Cancer 2003; 3 (06) 391-398
   Crossref PubMed Google Scholar
6.  National Center for Biotechnology Information. PubChem Compound Summary for CID 68029831, Trilaciclib. Accessed March 24, 2023 at:  https://pubchem.ncbi.nlm.nih.gov/compound/Trilaciclib
   Google Scholar
7.  Weiss J, Goldschmidt J, Andric Z. et al. Effects of trilaciclib on chemotherapy-induced myelosuppression and patient-reported outcomes in patients with extensive-stage small cell lung cancer: pooled results from three phase II randomized, double-blind, placebo-controlled studies. Clin Lung Cancer 2021; 22 (05) 449-460
   Crossref PubMed Google Scholar
8.  Dómine Gómez M, Csőszi T, Jaal J. et al. Exploratory composite endpoint demonstrates benefit of trilaciclib across multiple clinically meaningful components of myeloprotection in patients with small cell lung cancer. Int J Cancer 2021; 149 (07) 1463-1472
   Crossref PubMed Google Scholar
9.  Daniel D, Kuchava V, Bondarenko I. et al. Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: a multicentre, randomised, double-blind, placebo-controlled phase II trial. Int J Cancer 2021; 148 (10) 2557-2570
   Crossref PubMed Google Scholar

Address for correspondence

Publication History

Article published online:
30 April 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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References

1.  Lyman GH. Febrile neutropenia: an ounce of prevention or a pound of cure. J Oncol Pract 2019; 15 (01) 27-29
   Crossref PubMed Google Scholar
2.  Crawford J, Ozer H, Stoller R. et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 1991; 325 (03) 164-170
   Crossref PubMed Google Scholar
3.  Crawford J, Dale DC, Kuderer NM. et al. Risk and timing of neutropenic events in adult cancer patients receiving chemotherapy: the results of a prospective nationwide study of oncology practice. J Natl Compr Canc Netw 2008; 6 (02) 109-118
   Crossref PubMed Google Scholar
4.  Dinan MA, Hirsch BR, Lyman GH. Management of chemotherapy-induced neutropenia: measuring quality, cost, and value. J Natl Compr Canc Netw 2015; 13 (01) e1-e7
   Crossref PubMed Google Scholar
5.  Kubista E, Glaspy J, Ann Holmes F. et al Bone Pain Associated with Once-Per-Cycle Pegfilgrastim Is Similar to Daily Filgrastim in Patients with Breast Cancer. Clin Breast Cancer 2003; 3 (06) 391-398
   Crossref PubMed Google Scholar
6.  National Center for Biotechnology Information. PubChem Compound Summary for CID 68029831, Trilaciclib. Accessed March 24, 2023 at:  https://pubchem.ncbi.nlm.nih.gov/compound/Trilaciclib
   Google Scholar
7.  Weiss J, Goldschmidt J, Andric Z. et al. Effects of trilaciclib on chemotherapy-induced myelosuppression and patient-reported outcomes in patients with extensive-stage small cell lung cancer: pooled results from three phase II randomized, double-blind, placebo-controlled studies. Clin Lung Cancer 2021; 22 (05) 449-460
   Crossref PubMed Google Scholar
8.  Dómine Gómez M, Csőszi T, Jaal J. et al. Exploratory composite endpoint demonstrates benefit of trilaciclib across multiple clinically meaningful components of myeloprotection in patients with small cell lung cancer. Int J Cancer 2021; 149 (07) 1463-1472
   Crossref PubMed Google Scholar
9.  Daniel D, Kuchava V, Bondarenko I. et al. Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: a multicentre, randomised, double-blind, placebo-controlled phase II trial. Int J Cancer 2021; 148 (10) 2557-2570
   Crossref PubMed Google Scholar