Coverage Policy Manual
Policy #: 2021046
Category: Pharmacy
Initiated: March 2022
Last Review: December 2023
  Trilaciclib (e.g., Cosela)

Description:
Trilaciclib is a kinase inhibitor. Specifically, trilaciclib is a cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitor. It works by keeping hematopoietic stem and progenitor cells in the G1 phase of the cell cycle where cell division has just taken place and before DNA replication would begin again suppressing cell proliferation. It is administered prior to chemotherapy to preserve bone marrow and immune system function during chemotherapy. Trilaciclib is indicated to decrease the incidence of chemotherapy-induced myelosuppression in adult individuals when administered prior to a platinum/etoposide-containing regimen or topotecan-containing regimen for extensive-stage small cell lung cancer (Cosela, 2021).
 
Trilaciclib does not carry a black box warning. However, adverse reactions can occur. Trilaciclib can cause reactions at the injection-site such as phlebitis and thrombophlebitis. Acute drug hypersensitivity reactions (i.e., facial edema and urticaria) are also possible. CDK 4/6 inhibitors can also lead to severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis. Individuals should be monitored for cough, dyspnea, and hypoxia. Trilaciclib should be discontinued for recurrent moderate (Grade 2) ILD/pneumonitis. This medication can also cause fetal harm when administered to pregnant women (Cosela, 2021).
 
Regulatory Status
 
Cosela was approved by the U.S. Food and Drug Administration (FDA) on February 12, 2021 to reduce the incidence of chemotherapy-induced myelosuppression in adults receiving certain types of chemotherapy for extensive-stage small cell lung cancer (ES-SCLC).
 
Coding
 
See CPT/HCPCS Code section below.

Policy/
Coverage:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of trilaciclib for the treatment of chemotherapy-induced myelosuppression after receiving chemotherapy for ES-SCLC or any other condition, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, the use of trilaciclib for the treatment of chemotherapy-induced myelosuppression after receiving chemotherapy for ES-SCLC or any other condition is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
More than half of the patients diagnosed with extensive-stage small cell lung cancer (ES-SCLC) are 65 years of age or older at the time of diagnosis. Additionally, they often have comorbidities. The most common treatment includes use of platinum-based chemotherapy in combination with etoposide. This treatment can result in chemotherapy-induced myelosuppression (neutropenia, anemia, thrombocytopenia). Myelosuppression can lead to infection, sepsis, bleeding, fatigue, and increased cost of care to treat. Prevention of chemotherapy-induced myelosuppression is important. Chemotherapy indiscriminately kills proliferating cells including hematopoietic stem and progenitor cells (HSPCS) and immune cells. Arrest of CDK 4/6 dependent cells, which includes HCPSCS and lymphocytes, in the G1 phase of the cell cycle prevents them from proliferating in the presences of cytotoxic chemotherapy. Studies have shown that trilaciclib (Cosela), a cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitor, decreases the incidence of chemotherapy-induced myelosuppression in adult patients when administered prior to chemotherapy (Daniel, 2020).
 
A phase 1 in-human-trial (NCT02243150) was done to demonstrate the biological activity of trilaciclib and to define the starting dose level in combination with chemotherapy (Li, 2021). This was a single-center, single-dose, in-human study with healthy human volunteers between the ages of 18-60 with a BMI between 18-32. Thirty-three participants were enrolled. Twenty-four received trilaciclib and 9 received placebo. Twelve additional participants received a single 192mg/m2 dose to confirm the biologically effective dose. The trial resulted in inhibited bone marrow HSPCS proliferation with minimal toxicity. All moderate adverse events spontaneously resolved within 24 hours and no adverse events of severe or life-threatening intensity were reported. Further, the dose of 192 mg/m2 resulted in 100% G1 arrest for most cell types which was consistent with model predictions. 192 mg/m2 was identified as the biologically effective dose. Further, studies (NCT02514447, NCT02499770) led to an adjustment of the dose to 240 mg/m2.
 
Approval of trilaciclib was based on results from a pooled analysis of intent-to-treat datasets from 3 studies (NCT02499770; NCT03041311; NCT02514447) of patients with ES-SCLC. In these studies, a total of 242 patients were randomly assigned to receive standard chemotherapy plus either trilaciclib or placebo. The studies then compared the 2 groups for the proportion of patients with severe neutropenia and the duration of severe neutropenia in the first cycle of chemotherapy. In all 3 studies, patients who received trilaciclib had a lower chance of having severe neutropenia compared to patients who received a placebo. Among those who had severe neutropenia, patients who received trilaciclib, on average, had it for a shorter time than patients who received a placebo. Studies 1 and 2 included patients who were na├»ve to therapy, while Study 3 examined patients who had been on previous regimens.  
 
Across the 3 studies, 123 patients received trilaciclib prior to chemotherapy and 119 received placebo. When given prior to chemotherapy, trilaciclib significantly decreased induced myelosuppression and the need for supportive care interventions.
In ES-SCLC, trilaciclib showed statistically significant reductions in the duration of severe neutropenia, the percentage of patients who developed severe neutropenia, and the percentage of patients who required supportive care interventions, including G-CSFs, ESAs, and blood cell transfusions. However, it had a negligible statistical effect on disease progression and survival. The rate of hospitalizations due to chemotherapy-induced myelosuppression or sepsis was 13.6% in patients who received placebo versus 4% in patients who received trilaciclib prior to chemotherapy
 
Among those who had severe neutropenia, patients who received trilaciclib, on average, had it for a shorter time than patients who received a placebo. It is important to note that trilaciclib was studied against placebo and was not compared to current alternative therapies, granulocyte colony-stimulating factors (G-CSFs; filgrastim, pegfilgrastim), or erythropoiesis-stimulating agents (ESAs; epoetin, darbepoetin). In the pivotal trial, 35% of patients treated with trilaciclib still required G-CSFs (67% with placebo), and overall survival was similar.  Until there are trials identifying the utility of this drug in concert with existing therapies, the data is insufficient for trilaciclib to meet primary coverage criteria.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
J1448Injection, trilaciclib, 1mg
J3490Unclassified drugs

References: Cosela (trilaciclib) [prescribing information]. Durham, NC: G1 Therapeutics, Inc. 2021.

Durham, NC: G1 Therapeutics, Inc. 2021.(2021) Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: A multicenter, randomized, double-blind, placebo-controlled Phase II trial. International Journal of Cancer. 2020 Dec 21; https://onlinelibrary.wiley.com/doi/10.1002/ijc.33453 Accessed March 4, 2021.

Hart LL, Ferrarotto R, Andric ZG, et al.(2020) 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 Jan;38(1):350-365. doi: 10.1007/s12325-020-01538-0. Epub 2020 Oct 29.

Li C, Hart L, Owonikoko TK, et al.(2021) Trilaciclib dose selection: an integrated pharmacokinetic and pharmacodynamic analysis of preclinical data and Phase Ib/Iia studies in patients with extensive-stage small cell lung cancer. . Trilaciclib dose selection: an integrated pharmacokinetic and pharmacodynamic analysis of preclinical data and Phase Ib/IIa studies in patients with extensive-stage small cell lung cancer.

Weiss JM, Csoszi T, Maglakelidze M, et al.(2019) Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial. Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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