Trilaciclib (Cosela)

Number: 0988

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

---

Policy

Scope of Policy

This Clinical Policy Bulletin addresses trilaciclib (Cosela) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of trilaciclib (Cosela) is required of all Aetna participating providers and members in applicable plan designs. For precertification of trilaciclib (Cosela), call (866) 752-7021, or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification. 

1. Criteria for Initial Approval

   Extensive-stage Small Cell Lung Cancer

   Aetna considers trilaciclib (Cosela) medically necessary to decrease the incidence of chemotherapy-induced myelosuppression in adult members with extensive-stage small cell lung cancer when all of the following criteria are met:

   1. The member will be receiving either of the following chemotherapeutic regimens:

      1. A platinum/etoposide-containing regimen; or
      2. A topotecan-containing regimen; and
   2. The requested medication will be given within 4 hours prior to the start of chemotherapy on each day chemotherapy is administered; and
   3. The requested medication will not be used with granulocyte colony-stimulating factors (G-CSFs) and/or erythropoiesis-stimulating agents (ESAs) as primary prophylaxis during cycle 1.

   Aetna considers all other indications experimental, investigational, or unproven.

2. Continuation of Therapy

   Aetna considers continuation of trilaciclib (Cosela) therapy medically necessary for all members (including new members) requesting authorization who meet all initial selection criteria.

Dosage and Administration

Trilaciclib (Cosela) is available for injection as 300 mg of trilaciclib as a lyophilized cake in a single-dose vial for intravenous use only.

Small Cell Lung Cancer

The recommended dose of Cosela is 240 mg/m²as a 30-minute intravenous infusion completed within 4 hours prior to the start of chemotherapy on each day chemotherapy is administered. The interval between doses of Cosela on sequential days should not be greater than 28 hours.

Source: G1 Therapeutics, 2023

---

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
HCPCS codes covered if selection criteria are met:
J1448	Injection, trilaciclib, 1mg
ICD-10 codes covered if selection criteria are met:
D61.810 - D61.89	Other specified aplastic anemias and other bone marrow failure syndromes [chemotherapy-induced myelosuppression]
C34.00 - C34.92	Malignant neoplasm of bronchus and lung [Small cell lung cancer]

---

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Cosela is indicated to decrease the incidence of chemotherapy-induced myelosuppression in adult patients when administered prior to a platinum/etoposide-containing regimen or topotecan-containing regimen for extensive-stage small cell lung cancer (ES-SCLC).

Trilaciclib (Cosela) is a transient inhibitor of CDK 4 and 6. Hematopoietic stem and progenitor cells (HSPCs) in the bone marrow give rise to circulating neutrophils, RBCs, and platelets. HSPC proliferation is dependent on CDK4/6 activity (G1 Therapeutics, 2023).

Trilaciclib (Cosela) carries the following warnings and precautions:

• Injection-site reactions, including phlebitis and thrombophlebitis. Injection-site reactions including phlebitis and thrombophlebitis occurred in 56 (21%) of 272 patients receiving Cosela in clinical trials, including Grade 2 (10%) and Grade 3 (0.4%) adverse reactions (ARs) (G1 Therapeutics, 2023).
• Acute drug hypersensitivity reactions. Acute drug hypersensitivity reactions occurred in 16 (6%) of 272 patients receiving Cosela in clinical trials, including Grade 2 reactions (2%) (G1 Therapeutics, 2023). 
• Interstitial lung disease (ILD/pneumonitis). ILD/pneumonitis occurred in 1 (0.4%) of 272 patients receiving Cosela in clinical trials (G1 Therapeutics, 2023). 
• Embryo-fetal toxicity. Cosela can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should use an effective method of contraception during treatment with Cosela and for at least 3 weeks after the final dose (G1 Therapeutics, 2023).

Per the prescribing information, the most common adverse reactions (greater than or equal to 10% of persons with greater than or equal to 2% difference in incidence compared to placebo) were fatigue, hypocalcemia, hypokalemia, hypophosphatemia, aspartate aminotransferase increased, headache, and pneumonia.

Small Cell Lung Cancer

In the United States, approximately 30,000 small cell lung cancer (SCLC) patients are treated on a yearly basis. SCLC is one of the two main types of lung cancer, and is responsible for about 10% to 15% of all lung cancers. SCLC is an invasive disease and tends to grow and spread more quickly than non-small cell lung cancer (NSCLC). It is usually asymptomatic; once symptoms are noticeable, it is often indicative that the cancer has spread to other parts of the body. About 70% of people with SCLC will have cancer that has spread at the time of diagnosis. The severity of symptoms usually corresponds with increased cancer growth and spread. From the time of diagnosis, the approximate 5-year survival rate for people with SCLC is 6%. The five-year survival rates for limited-stage (the cancer is confined to one side of the chest) SCLC is 12% to 15%, and for extensive stage (cancer that has metastasized to the other lung and beyond), survival rates are less than 2%. Chemotherapy is the usual treatment for extensive-stage small cell lung cancer (ES-SCLC) (G1 Therapeutics, 2021c).

Chemotherapy is an effective and important treatment modality against cancer. However, chemotherapy does not discriminate between healthy cells and cancer cells. It destroys both, including important hematopoietic stem and progenitor cells (HSPCs) in the bone marrow that manufacture white blood cells (immune cells that help fight infection), red blood cells (cells that carry oxygen from the lungs to the tissues), and platelets (cells that prevent bleeding from cancer, surgeries, chronic diseases, and injuries). This chemotherapy-induced bone marrow destruction, known as myelosuppression, can lead to increased risk of infection, anemia, thrombocytopenia, and other complications. Myeloprotection is a new strategy of protecting HSPCs in the bone marrow from chemotherapy-induced damage. This approach can help lessen some chemotherapy-related toxicity, making chemotherapy safer and more tolerable, while also minimizing the need for reactive rescue interventions (G1 Therapeutics, 2021c).

On February 12, 2021, the FDA approved Cosela (trilaciclib) for injection to decrease the incidence of chemotherapy-induced myelosuppression in adult patients when administered prior to a platinum/etoposide-containing regimen or topotecan-containing regimen for extensive-stage small cell lung cancer (ES-SCLC). It is the first therapy in its class with a novel approach to help protect bone marrow (myeloprotection) when given prior to chemotherapy treatment. Cosela received FDA Priority Review and Breakthrough Therapy designations for the previously noted indication. The approval of Cosela was established on data from three randomized, placebo-controlled trials that showed patients receiving Cosela prior to the start of chemotherapy had a clinically meaningful and statistically significant decrease in the duration and severity of neutropenia (FDA, 2021; G1 Therapeutics, 2021c).

One clinical trial consisted of a randomized (1:1), double-blind, placebo-controlled study of Cosela or placebo administered prior to treatment with etoposide, carboplatin, and atezolizumab (E/P/A) not previously treated with chemotherapy. A total of 107 patients were randomized to receive Cosela (n=54) or placebo (n=53) prior to administration of E/P/A. Carboplatin (AUC 5) and atezolizumab (1200 mg) were administered on day 1 and etoposide (100 mg/m²) and Cosela (240 mg/m²) or placebo were administered on days 1, 2, and 3 of a 21-day cycle for a maximum of 4 cycles (induction). After induction, maintenance atezolizumab (1200 mg) monotherapy on day 1 of a 21-day cycle continued until disease progression or unacceptable toxicity. Cosela was not administered during maintenance. The mean relative dose intensities (RDIs) for E/P/A in patients receiving Cosela were 93%, 95%, and 93%, respectively. The mean RDIs for E/P/A in patients receiving placebo were 88%, 89%, and 91%, respectively. The study showed a statistically shorter duration of severe neutropenia in cycle 1 (0 vs 4 days) and a smaller proportion of patients with severe neutropenia (2% vs 49%). Nineteen percent of patients receiving Cosela had Grade 3 or 4 decreased hemoglobin compared with 28% of patients receiving placebo (adjusted relative risk 0.663 [95% CI: 0.336, 1.310]) (G1 Therapeutics, 2021a; 2023). 

Another clinical trial involved a randomized (1:1), double-blind, placebo-controlled evaluation Cosela or placebo administered prior to treatment with etoposide and carboplatin (E/P) for patients with newly diagnosed ES-SCLC not previously treated with chemotherapy. A total of 77 patients were randomized to Cosela (n=39) or placebo (n=38). Carboplatin (AUC 5) was administered on Day 1 and etoposide (100 mg/m²) and Cosela (240 mg/m²) or placebo were administered on days 1, 2, and 3 of a 21-day cycle until disease progression of unacceptable toxicity. Ten percent of patients receiving Cosela had Grade 3 or 4 decreased hemoglobin compared with 18% of patient receiving placebo (G1 Therapeutics, 2021a; 2023).

An additional clinical trial included a randomized, double-blind, placebo-controlled evaluation of Cosela or placebo administered prior to topotecan in patients with extensive-stage small cell lung cancer (ES-SCLC) previously treated with chemotherapy. A total of 61 patients were randomized to Cosela (n=32) or placebo (n=29). Topotecan (1.5 mg/m2) and Cosela (240 mg/m2) or placebo were administered on days 1-5 of a 21-day cycle. Treatment was administered until disease progression or unacceptable toxicity. Thirty-eight percent of patients receiving Cosela had Grade 3 or 4 decreased hemoglobin compared with 59% of patients receiving placebo (G1 Therapeutics, 2021a; 2023).

Triple-Negative Breast Cancer

Tan and colleagues (2022) reported final anti-tumor results from a phase-II clinical trial of trilaciclib administered before gemcitabine plus carboplatin (GCb) in patients with metastatic triple-negative breast cancer (TNBC).  Patients were randomized (1:1:1) to group 1 [GCb (days 1, 8); n = 34], group 2 [trilaciclib before GCb (days 1, 8); n = 33], or group 3 [trilaciclib (days 1, 8) and trilaciclib before GCb (days 2, 9); n = 35].  Subgroup analyses were carried out according to CDK4/6 dependence, level of programmed death-ligand 1 (PD-L1) expression, and RNA-based immune signatures using proportional hazards regression.  T-cell receptor (TCR) β CDR3 regions were amplified and sequenced to identify, quantify, and compare the abundance of each unique TCRβ CDR3 at baseline and on treatment.  Median overall survival (OS) was 12.6 months in group 1, not reached in group 2 (HR = 0.31; p = 0.0016), 17.8 months in group 3 (hazard ratio [HR] = 0.40; p = 0.0004), and 19.8 months in groups 2 and 3 combined (HR = 0.37; p < 0.0001).  Efficacy outcomes were comparable regardless of cancer CDK4/6 dependence status and immune signatures.  Administering trilaciclib before GCb prolonged OS irrespective of PD-L1 status but had greater benefit in the PD-L1-positive population.  T-cell activation was enhanced in patients receiving trilaciclib.  The authors concluded that the findings of this study suggested that administration of trilaciclib before GCb improved OS among patients with metastatic TNBC (mTNBC), with a more pronounced effect in patients with more immunogenic tumors.  These researchers hypothesized that the effects of trilaciclib on anti-tumor immunity are 2-fold: First, the protection of lymphocyte populations from chemotherapy-induced damage; and second, the enhancement of T-cell immunity via multiple mechanisms, including increased antigen presentation, enhanced T-cell activation, and a more robust clonal expansion of T cells.

The authors stated that drawbacks of this study included the small sample size, which meant that only large differences in OS and PFS would be detected.  Moreover, anti-tumor efficacy outcomes were not the primary study endpoints.  The sample size was powered to show superiority of group 3 over group 1 for at least 1 primary endpoint (duration of severe neutropenia in cycle 1 or occurrence of severe neutropenia during the treatment period).  As such, comparisons of secondary endpoints (objective response rate [ORR], progression free survival [PFS], and OS) should be considered exploratory and interpreted with caution.  Subgroup analyses according to CDK4/6 dependence were also exploratory.  Furthermore, use of the doublet GCb backbone may restrict extrapolation to patients with mTNBC receiving single-agent chemotherapy.  The observed immune effects of trilaciclib are also not yet fully understood and require further study in clinical trials.  Nonetheless, these findings are hypothesis- generating, prompting further study into the association between enhanced anti-tumor immunity and improved OS among patients with mTNBC receiving trilaciclib and chemotherapy.  A pivotal phase-III clinical trial of trilaciclib or placebo in combination with 1st- or 2nd-line GCb in patients with locally recurrent unresectable TNBC, or mTNBC is underway, with OS as the primary endpoint.  Trilaciclib will be evaluated in the 1st-line setting regardless of PD-L1 status, and in the 2nd-line setting following progression on a PD-1/PD-L1 inhibitor in 2 independent cohorts.  Exploratory endpoints will examine pharmacodynamic parameters, including those related to immune-based mechanisms.

Trilaciclib Before Gemcitabine plus Carboplatin for Metastatic Triple-Negative Breast Cancer

Goel et al (2022) stated that triple-negative breast cancer (TNBC) is an aggressive malignancy for which cytotoxic chemotherapy remains the mainstay of treatment.  Trilaciclib is an intravenous (IV) cyclin-dependent kinase 4/6 inhibitor that induces transient cell cycle arrest of hematopoietic stem and progenitor cells and immune cells during chemotherapy exposure, protecting them from chemotherapy-induced damage and enhancing immune activity.  Administration of trilaciclib before gemcitabine plus carboplatin (GCb) significantly improved OS compared with GCb alone in an open-label, phase-II clinical trial in patients with metastatic TNBC, potentially via protection and direct activation of immune function.  The authors noted that the randomized, double-blind, placebo-controlled, phase-III PRESERVE 2 Trial will examine the safety and effectiveness of trilaciclib administered before GCb in patients with locally advanced unresectable or metastatic TNBC.

---

References