Trilaciclib Reduces Need for G-CSF, RBC Transfusions From Chemo-Induced AEs in ES-SCLC

Renata Ferrarotto, MD

Treatment with the CDK4/6 inhibitor trilaciclib prior to chemotherapy compared with placebo significantly reduced the need for supportive care interventions in the management of severe neutropenia and grade 3/4 anemia induced by chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC), according to pooled findings from 3 studies presented at the 2020 North America Conference on Lung Cancer.

Results, which were from 3 randomized, double-blind, placebo-controlled trials, showed that the reductions were observed irrespective of growth-colony stimulating factor (G-CSF) administration. Additionally, hospitalizations due to chemotherapy-induced myelosuppression or sepsis were fewer and less frequent in those with ES-SCLC who received the agent versus placebo.

“The results of this study showed that administering trilaciclib prior to chemotherapy was effective in reducing chemotherapy-induced myelosuppression, resulting in the need for fewer supportive care interventions, fewer chemotherapy dose modifications, and an improvement in patients’ quality of life,” Renata Ferrarotto, MD, an associate professor, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, said in a presentation during the meeting.

Multilineage myelosuppression is found to be a significant dose-limiting and life-threatening complication from chemotherapy, which ultimately causes delays and reductions in dosage, as well as comprises long-term outcomes for patients. The toxicities also impact patient safety and quality of life, while increasing health care costs and hospitalizations, Ferrarotto explained.

Currently, there are no available treatments to prevent chemotherapy-induced myelosuppression across lineages. G-CSFs, ESAs, and blood transfusions are individualized treatments while harboring risks and limitations.

Trilaciclib is a transient CDK4/6 inhibitor that is given intravenously (IV) prior to chemotherapy and arrests hematopoietic stem and progenitor cells (HSPCs) in the G1 phase of the cell cycle during exposure to chemotherapy. Moreover, cell cycle arrest is transient due to daily dosing and trilaciclib’s short half-life. Preserved HSPCs do resume activity following chemotherapy. 

In the analysis presented during the meeting, data were pooled from 3 randomized, double-blind, placebo-controlled studies that were conducted to evaluate the impact of myelosuppression from trilaciclib (n = 123) versus placebo (n = 119) when given to patients with ES-SCLC. The authors noted that the pooled findings, which were supported by the Breslow-Day test, allowed for greater statistical precision.

In the first study, G1T28-02 (NCT02499770), patients with newly diagnosed ES-SCLC received trilaciclib at 240 mg/m2 or placebo IV, both daily, prior to chemotherapy on days 1 to 3 of each 21-day etoposide/carboplatin IV cycle.

The second trial, G1T28-05 (NCT03041311), comprised patients with newly diagnosed ES-SCLC who received either 240 mg/m2 of daily trilaciclib or placebo before chemotherapy on days 1 to 3 of each 21-day cycle of etoposide/carboplatin/atezolizumab (Tecentriq) cycle for up to 4 cycles, followed by single-agent atezolizumab without trilaciclib/placebo every 21 days.

In the third study, G1T28-03 (NCT02514447), patients with previously treated ES-SCLC in the second- or third-line setting, received trilaciclib at 240 mg/m2 or placebo daily prior to topotecan at 1.5 mg/m2 IV daily on days 1 to 5 of each 21-day cycle.

Investigators sought to summarize the utilization of G-CSFs, ESAs, and red blood cell (RBC) transfusions as well as hospitalizations due to chemotherapy-induced myelosuppression or sepsis, as well as to evaluate the relationship between supportive care interventions and the benefits with myelopreservation from trilaciclib.

Data were collected during the first 4 treatment cycles, and were summarized by the presence or absence of G-CSF administration. There was also established concordance and association between grade 3/4 anemia, RBC transfusions on/after week 5, and ESA administration.

The primary end points were percentage of patients with severe (grade 4) neutropenia and duration of severe neutropenia, while supportive care end points were percentage of patients with RBC transfusions on/after week 5 and number of RBC transfusion events on/after week 5, and also the percentage of patients receiving ESAs.

Investigators also explored the percentage of patients with hospitalizations, and the incidence of hospitalizations, due to chemotherapy-induced myelosuppression or sepsis.

Results showed that fewer patients on trilaciclib than placebo had severe neutropenia or grade 3/4 anemia, and there was a reported reduction with supportive care interventions.

The median duration of severe neutropenia in cycle 1 was 4 days (P <.0001) and only occurred in the placebo arm, and the percentage of patients with severe neutropenia on trilaciclib and placebo were 11.4% and 52.9%, respectively. Moreover, the patients on trilaciclib versus placebo who had G-CSF administration was 28.5% and 56.3%, respectively (P <.0001), and the rates of grade 3/4 anemia occurred in 20.3% and 31.9% of patients, respectively (P = .0279).

Additionally, 14.6% of patients on trilaciclib versus 26.1% of those on placebo had RBC transfusions on/after week 5, and 1.5% and 3.1% of patients, respectively, had an event rate per 100 weeks of RBC transfusions at this time point (P = .0027). A total 3.3% of patients on trilaciclib and 11.8% of those on placebo received ESAs (P = .0252).

Regarding hospitalizations due to chemotherapy-induced myelosuppression or sepsis, patients on the trilaciclib arm experienced significantly less of such events at 4.1% and 13.6%, respectively (P = .0088). The incidence of hospitalizations due to chemotherapy-induced myelosuppression or sepsis was 0.94% of those on trilaciclib and 5.7% of those on placebo (P = .0055).

The percentage of patients with all-cause hospitalization were similar at 24.6% and 25.4%, respectively; incidence occurred in 8.44% and 11.98% of the trilaciclib- and placebo-treated patients, respectively.

Also, across cycles, the proportion of patients with RBC transfusions was lower in the trilaciclib arm versus placebo arm, at cycle 1 (7.3% vs 8.4%, respectively), cycle 2 (6.4% vs 10.3%), cycle 3 (8.3% vs 14.3%), and cycle 4 (5.8% vs 14.3%).

Furthermore, while RBC transfusions and ESA administrations were linked with grade 3/4 anemia, the anemia did not frequently lead to ESA administration.

In the trilaciclib arm, 13.0% of patients with grade 3/4 anemia had RBC transfusions on/after week 5, and 7.3% of those without RBC transfusion experienced the AE. Additionally, grade 3/4 anemia occurred in 2.4% of patients with ESA administration and in 17.9% of patients who did not have ESA therapy.

In the placebo arm, grade 3/4 anemia occurred in 24.4% and 7.6% of patients with and without RBC transfusion on/after week 5, and in 10.1% and 21.8% of those with and without ESA administration.

Investigators also analyzed patients with grade 3/4 anemia in a pooled efficacy analysis set who were treated with trilaciclib (n = 25) or placebo (n = 38). On the trilaciclib arm, of 3 patients who had ESA therapy, all had RBC transfusion on/after week 5. In the placebo group of which 12 patients had ESA administration, 23.7% of patients had RBC transfusions on/after week 5 and 7.9% did not.

“These data are especially pertinent considering the current health care environment, which has created additional challenges in the management of myelosuppression, which [includes] limited blood supply, infection risk, and the need to minimize patient exposure in hospitalizations,” concluded Ferrarotto. “By preventing chemotherapy-induced myelosuppression, and reducing the need for associated supportive care and hospitalizations, trilaciclib has the potential to improve the management and quality of life of small cell lung cancer patients receiving myelosuppressive chemotherapy.”

Reference

Ferrarotto R, Anderson I, Medgyasszay B, et al. Trilaciclib reduces the need for growth factors and red blood cell transfusions to manage chemotherapy-induced myelosuppression. Presented at: IASLC 202 North America Conference on Lung Cancer; October 16-17, 2020; virtual. https://bit.ly/3kgDOzM.