On February 12, 2021, the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor trilaciclib was approved for use 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 (SCLC).^1,2

Supporting Efficacy Data

Approval was based on findings in three double-blind, placebo-controlled trials in patients with extensive-stage SCLC^2-5: G1T28-05 (ClinicalTrials.gov identifier NCT03041311),³ G1T28-02 (NCT02499770),⁴ and G1T28-03 (NCT02514447).⁵ All three studies prohibited primary prophylactic granulocyte–colony stimulating factor (G-CSF) and erythropoiesis-stimulating agent use during cycle 1 of treatment. Both erythropoiesis-stimulating agents and prophylactic G-CSF were allowed from cycle 2 onward as clinically indicated and therapeutic G-CSF, red blood cell, and platelet transfusions were allowed at any time during the studies as clinically indicated.

In GIT28-05, 107 newly diagnosed patients with no prior chemotherapy were randomly assigned to receive intravenous (IV) trilaciclib at 240 mg/m² (n = 54) or placebo (n = 53) on days 1, 2, and 3 of 21-day cycles for a maximum of four cycles prior to administration of etoposide, carboplatin, and atezolizumab. For the primary endpoints, trilaciclib was associated with reduced mean duration of severe neutropenia during cycle 1 (0 vs 4 days, P < .0001) and a reduced proportion of patients developing severe neutropenia (2% vs 49%, P < .0001). The event rates per cycle for all-cause chemotherapy dose reductions were 0.021 vs 0.085. Proportions of patients with red blood cell transfusions at ≥ 5 weeks were 13.0% vs 20.8% and proportions with G-CSF administration were 29.6% vs 47.2%.

In G1T28-02, 77 newly diagnosed patients with no prior chemotherapy were randomly assigned to receive trilaciclib at 240 mg/m² (n = 39) or placebo (n = 38) on days 1, 2, and 3 of 21-day cycles prior to treatment with etoposide and carboplatin, with treatment continued until disease progression or unacceptable toxicity. Mean duration of severe neutropenia during cycle 1 was 0.5 vs 3 days, proportions of patients developing severe neutropenia were 5.1% vs 42.1%, event rates per cycle for all-cause chemotherapy dose reductions were 0.0022 vs 0.084, proportions of patients with red blood cell transfusions at ≥ 5 weeks were 5.1% vs 23.7%, and proportions with G-CSF administration were 10.3% vs 63.2%.

In G1T28-03, 61 patients previously treated with chemotherapy were randomly assigned to receive trilaciclib at 240 mg/m² (n = 32) or placebo (n = 29) on days 1 to 5 of 21-day cycles prior to administration of topotecan, with treatment continued until disease progression or unacceptable toxicity. The mean duration of severe neutropenia during cycle 1 was 2 vs 7 days, proportions of patients developing severe neutropenia were 40.6% vs 75.9%, and event rates per cycle for all-cause chemotherapy dose reductions were 0.051 vs 0.116.

How It Works

Trilaciclib is a transient inhibitor of CDK 4 and 6. Hematopoietic stem and progenitor cells in the bone marrow give rise to circulating neutrophils, red blood cells, and platelets. Hematopoietic stem and progenitor cells proliferation is dependent on CDK4/6 activity.

How It Is Used

The recommended dose of trilaciclib is 240 mg/m² per dose as a 30-minute IV infusion completed within 4 hours prior to the start of chemotherapy on each day chemotherapy is administered. If trilaciclib is discontinued, chemotherapy should not be resumed until ≥ 96 hours after the last dose of trilaciclib.

Prescribing information provides instructions on dose modification, including withholding, discontinuing, or altering administration of trilaciclib, for adverse reactions including injection-site reactions, encompassing phlebitis and thrombophlebitis; acute drug hypersensitivity reactions; interstitial lung disease/pneumonitis; and other grade 3 or 4 toxicities.

Concomitant use of trilaciclib with certain OCT2, MATE1, and MATE-2K substrates should be avoided when increased minimal concentrations of such substrates may lead to serious or life-threatening toxicities. Trilaciclib is an inhibitor of OCT2, MATE1, and MATE-2K. Coadministration may increase the concentration or net accumulation of OCT2, MATE1, and MATE-2K substrates in the kidney (eg, dofetilide, dalfampridine, and cisplatin).

Safety Profile

Safety data are pooled from a total of 122 patients receiving trilaciclib and 118 receiving placebo in the G1T28-05, G1T28-02, and G1T28-03 trials. Overall, 71% vs 78% of patients completed at least four cycles of therapy; the median duration of treatment was four cycles in both groups.

Adverse events of any grade that occurred in ≥ 10% of the trilaciclib group with a ≥ 2% higher incidence vs placebo patients were fatigue (34% vs 27%), hypocalcemia (24% vs 21%), hypokalemia (22% vs 18%), hypophosphatemia (21% vs 16%), increased aspartate aminotransferase (17% vs 14%), headache (13% vs 9%), and pneumonia (10% vs 8%).The most common grade 3 or 4 adverse events in patients receiving trilaciclib included pneumonia (7% vs 7% in placebo group), hypophosphatemia (7% vs 2%), and hypokalemia (6% vs 3%). Grade 3 or 4 hematologic adverse events occurring in patients receiving trilaciclib vs placebo included neutropenia (32% vs 69%), febrile neutropenia (3% vs 9%), anemia (16% vs 34%), thrombocytopenia (18% vs 33%), leukopenia (4% vs 17%), and lymphopenia (< 1% vs < 1%).

Serious adverse events occurred in 30% of patients receiving trilaciclib, with those occurring in > 3% consisting of respiratory failure, hemorrhage, and thrombosis. Infusion interruptions due to an adverse event occurred in 4% of patients. Adverse events led to permanent discontinuation of any drug in 9% of patients receiving trilaciclib, with causes consisting of pneumonia (2%), asthenia (2%), injection-site reaction, thrombocytopenia, cerebrovascular accident, ischemic stroke, infusion-related reaction, respiratory failure, and myositis (< 1% each). Adverse events led to death in 5% of patients, with causes including pneumonia (2%), respiratory failure (2%), acute respiratory failure (< 1%), hemoptysis (< 1%), and cerebrovascular accident (< 1%).

Trilaciclib labeling has warnings/precautions for injection-site reactions, including phlebitis and thrombophlebitis; acute drug hypersensitivity reactions; interstitial lung disease/pneumonitis; and embryofetal toxicity. Infusion should be stopped and treatment permanently discontinued for severe or life-threatening injection-site reactions. Patients should be monitored for signs and symptoms of acute drug hypersensitivity reactions, including edema (facial, eye, and tongue), urticaria, pruritus, and anaphylactic reactions; treatment should be permanently discontinued for severe or life-threatening reactions. Treatment should be permanently discontinued for recurrent symptomatic or severe/life-threatening interstitial lung disease/pneumonitis. Patients should be advised not to breastfeed while receiving trilaciclib.

REFERENCES

1. U.S. Food and Drug Administration: FDA approves drug to reduce bone marrow suppression caused by chemotherapy. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-drug-reduce-bone-marrow-suppression-caused-chemotherapy. Accessed March 4, 2021.

2. Cosela (trilaciclib) for injection, for intravenous use, prescribing information, G1 Therapeutics, Inc, February 2021. Available at https://www.cosela.com/?gclid=CjwKCAiAg8OBBhA8EiwAlKw3kkl0RRMzfHyz9xw1_aSAaLNu1bfn9ee4QYWOBF4qlFDM3qlesmawJxoCPAgQAvD_BwE. Accessed March 4, 2021.

3. 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. December 21, 2020 (early release online).

4. Weiss JM, Csoszi T, Maglakelidze M, et al: 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. Ann Oncol 30:1613-1621, 2019.

5. 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 38:350-365, 2021.