Trilaciclib Protects Against Chemotherapy-Induced Myelosuppression

Myelosuppression is one of the most common and dangerous doselimiting toxicities of traditional chemotherapy.

Chemotherapy-induced myelosuppression (CIM) can cause clinically significant sequelae, including bleeding, fatigue, and potentially fatal infections. Historically, CIM has been managed with transfusions, chemotherapy dose delays, dose reductions, and drugs.

Pharmacologic management of CIM has consisted of administering growth factors, including erythropoietin-stimulating agents (ESAs) and granulocyte colony-stimulating factors (G-CSFs). By stimulating the production of erythrocytes and neutrophils, respectively, these agents promote bone marrow recovery after chemotherapy administration. Despite their proven clinical benefit, risks and toxicities exist, ranging from bone pain with G-CSFs to an increase in thrombotic events with ESAs. The risks of these agents must be weighed against their clinical benefits.

In 2021, the FDA approved trilaciclib (Cosela, G1 Therapeutics) to prevent CIM in patients with extensive-stage small cell lung cancer (ES-SCLC). Trilaciclib reversibly inhibits cyclin-dependent kinase (CDK) 4/6 and arrests hematopoietic stem cells (HSCs) in the G1 phase of the cell cycle.¹ Contrary to growth factors that promote HSC production after chemotherapy, trilaciclib protects HSCs from the cytotoxic effects of chemotherapy during chemotherapy exposure. This mechanism has been used by other CDK 4/6 inhibitors, including abemaciclib (Verzenio), palbociclib (Ibrance), ribociclib (Kisqali) in the management of breast cancer. However, trilaciclib is the first CDK 4/6 inhibitor approved for a supportive-care indication.

Trilaciclib was approved to prevent CIM specifically in patients with ES-SCLC receiving chemotherapy regimens containing a platinum/etoposide or topotecan. These indications are based on results of 3 randomized phase 2 trials enrolling patients with ES-SCLC receiving treatment with 1 of 3 regimens: first-line carboplatin plus etoposide; first-line carboplatin plus etoposide plus atezolizumab; or second-line or third-line topotecan.^2-4 In each trial, patients were randomly assigned to receive trilaciclib 240 mg/m2 intravenously daily or a placebo, given prior to chemotherapy infusions. The primary end points in each trial were duration of severe neutropenia during cycle 1 of chemotherapy and percentage of patients with severe neutropenia during treatment. Severe neutropenia was defined as an absolute neutrophil count of less than 0.5 Å~ 109 cells/L, which is classified as a grade 4 toxicity by Common Terminology Criteria for Adverse Events version 4.03.¹

Across the 3 trials, 242 patients were randomly assigned to receive either trilaciclib (n = 123) or placebo (n = 119) prior to chemotherapy. Patients receiving trilaciclib had significant improvements in both primary outcomes, with a lower percentage of patients experiencing severe neutropenia (11.4% vs 52.9%, P < .0001) and a shorter mean duration of severe neutropenia during cycle 1 (0 days vs 4 days, P < .0001).¹ The trilaciclib group also had improved secondary outcomes, including improvements in the rates of grade 3 to 4 anemia, grade 3 to 4 thrombocytopenia, G-CSF administration, and ESA administration.¹

The pooled safety analysis from the 3 trials showed that the majority of patients in both groups had at least 1 adverse event (AE): 94.3% with trilaciclib vs 96.6% with the placebo.¹ The most common AEs reported with trilaciclib were aspartate aminotransferase elevation, fatigue, headache, hypocalcemia, hypokalemia, hypophosphatemia, and pneumonia.⁵ Less common but still-notable reactions in the trilaciclib group were injection site reactions (13.9% vs 2.5% in the placebo group), phlebitis or thrombophlebitis (9.0% vs 0.8%), and hypersensitivity reactions (4.1% vs 3.4%).¹ Compared with 3 patients in the placebo group, 6 patients in the trilaciclib group had fatal AEs, including cerebrovascular accident, hemoptysis, pneumonia, and respiratory failure.¹ The FDA approved trilaciclib with a warning for pulmonary toxicity, a warning that other CDK 4/6 inhibitors also carry in their labeling.^5-8

Because of its mechanism in arresting cell cycle progression, it is important to investigate any effects of trilaciclib on tumor response rates and concerns for tumor progression. Fortunately, the pooled analysis of the 3 trials suggested that tumor response rates were similar between trilaciclib and the placebo, with objective responses achieved in 49.1% of patients taking trilaciclib vs 51.8% of those taking the placebo.¹ Median durations of response, overall survival, and progression-free survival also were considered to be similar between the 2 groups.

The choice of investigating the use of trilaciclib in patients with ES-SCLC was deliberate. Because of their loss of the retinoblastoma protein, SCLC tumor cells do not depend on CDK 4/6 for replication.^1,2 Therefore, inhibition of the CDK 4/6 enzyme with trilaciclib would selectively arrest the replication of healthy cells and not affect SCLC tumor cells. Future studies investigating the use of trilaciclib to prevent CIM will require careful consideration in select tumor types that replicate outside of the CDK 4/6 pathway.

Trilaciclib was approved at the same dose investigated in the trials of 240 mg/m2 as a 30-minute intravenous infusion prior to chemotherapy administration. Trilaciclib should be administered on each day that chemotherapy is given and must be completed within 4 hours prior to the start of chemotherapy infusion.⁵ An inline 0.2- or 0.22-μm filter is required during trilaciclib administration.⁵

Conclusion

The approval of trilaciclib to prevent CIM marks an exciting new development for patients with ES-SCLC. However, data are limited to phase 2 trials. Therefore, larger, more robust phase 3 trials are needed to confirm these results and determine any clinical implications. Additionally, the benefit of trilaciclib is limited to patients with ES-SCLC because of the cells’ independence from the CDK4/6 pathway. Time will tell if any additional tumor types would be candidates for this novel therapy in preventing CIM.

About the Author

Bryan P. Fitzgerald, PharmD, BCOP, is a clinical specialist in oncology at the University of Rochester Specialty Pharmacy in New York.

References

1. 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(5):449-460. doi:10.1016/j.cllc.2021.03.010

2. 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. 2020;148(10):2557-2770. doi:10.1002/ijc.33453

3. Weiss JM, Csoszi T, Maglakelidze M, et al. Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving fi rst-line chemotherapy: a phase Ib/randomized phase II trial. Ann Oncol. 2019;30(10):1613-1621. doi:10.1093/annonc/mdz278

4. Hart LL, Ferrarotto R, Andric ZG, et al. Myelopreservation with trilaciclib in patients receiving topotecan for small cell lung cancer: results from a randomized, double-blind, placebo-controlled phase II study. Adv Ther. 2021;38(1):350-365. doi:10.1007/s12325-020-01538-0

5. Cosela (trilaciclib). Prescribing information. G1 Therapeutics Inc; 2021. Accessed June 30, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214200s000lbl.pdf

6. Ibrance (palbociclib). Prescribing information. Pfizer Inc; 2019. Accessed June 30, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/207103s008lbl.pdf

7. Kisqali (ribociclib). Prescribing information. Novartis Pharmaceuticals Corporation; 2021. Accessed June 30, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209092s004lbl.pdf

8. Verzenio (abemaciclib). Prescribing information. Lilly USA, LLC; 2021. Accessed June 30, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208716s000lbl.pdf