CDK4/6 Inhibitor in SCLC Cuts Chemo-Induced Myelosuppression

CDK4/6 inhibition before chemotherapy reduced the risk of severe neutropenia in patients with small cell lung cancer (SCLC), pooled data from three randomized trials showed.

Among 242 patients with extensive-stage SCLC, 11.4% of those receiving trilaciclib prior to each chemotherapy infusion experienced severe neutropenia over the first four cycles of treatment, as compared to 52.9% of those assigned to placebo (P<0.0001), reported Renata Ferrarotto, MD, of MD Anderson Cancer Center in Houston.

And the average duration of severe neutropenia was 0 versus 4 days (P<0.0001), respectively, according to findings presented at the virtual North America Conference on Lung Cancer.

Damage of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow due to chemotherapy leads to multilineage myelosuppression, explained Ferrarotto, and represents a significant burden to patients, often resulting in chemotherapy dose delays or reductions. Supportive care interventions typically include granulocyte colony stimulating factor (G-CSF), erythropoiesis-stimulating agents (ESAs), and blood transfusions after signs appear.

“Compared with placebo, trilaciclib administered prior to chemotherapy consistently prevented chemotherapy-induced neutropenia, regardless of G-CSF administration,” said Ferrarotto.

In the data presented, G-CSF was less frequently needed in patients who received trilaciclib (28.5% vs 56.3% with placebo, P<0.0001), as were ESAs (3.3% vs 11.8%, P=0.0252).

Grade 3/4 anemia was lower in the trilaciclib arm (20.3% vs 31.9%, P<0.0001) and fewer patients treated with the investigational CDK4/6 inhibitor required red blood cell transfusions (14.6% vs 26.1% with placebo, P=0.0254). The number of patients needing transfusions increased over time in the placebo group, but remained constant in the group receiving trilaciclib.

“In addition to the reduced need for supportive care interventions, fewer patients in the trilaciclib group were hospitalized due to chemotherapy-induced myelosuppression or sepsis,” said Ferrarotto. “This data is especially pertinent considering the current healthcare environment, which has created additional challenges in the management of myelosuppression due to limited blood supply, infection risk, and the need to minimize patient exposure and hospitalizations.”

Only 4.1% of patients in the trilaciclib arm were hospitalized because of chemotherapy-induced myelosuppression (neutropenia, anemia, thrombocytopenia) or sepsis, compared with 13.6% in the placebo arm (P=0.0088).

But discussant Melina Marmarelis, MD, of the University of Pennsylvania in Philadelphia, called attention to the fact that while trilaciclib led to fewer hospitalizations related to myelosuppression, it did not have any effect on the overall proportion of patients who were hospitalized (about a quarter of patients in each arm).

“Treatment of myelosuppression in small cell lung cancer has a long history,” said Marmarelis. “Studies in small cell led to the approval of G-CSF based on a decrease in neutropenic fever incidence. These studies did not show an overall survival benefit for patients using G-CSF, even if it allowed for increased doses of chemotherapy.”

While clinical outcome data were not reported in the pooled analysis, Marmarelis pointed to a previous randomized trial of chemotherapy with or without trilaciclib in SCLC that demonstrated no difference in progression-free survival (PFS) or overall survival (OS) with the agent.

“This is in line with previous G-CSF studies that showed count improvement, but no improvement in clinical outcomes,” she said. “Despite the lack of benefit in PFS or OS, patients reported a better experience with chemotherapy while receiving trilaciclib.”

National Comprehensive Cancer Network guidelines do not currently recommend G-CSF for primary prevention of myelosuppression in standard SCLC regimens, said Marmarelis, though G-CSF was not studied with current chemoimmunotherapy regimens and G-CSF also does not affect red blood cells or platelets.

“Protection of additional cell lines where treatment of cytopenias would generally include a transfusion is particularly important right now, as we try to minimize the contact that our vulnerable patients have with the healthcare system during the COVID-19 pandemic,” she said.

Ferrarotto presented data from three trials that tested trilaciclib in patients with extensive-stage SCLC receiving first-line chemotherapy, first-line chemoimmunotherapy, and salvage topotecan. Primary efficacy endpoints included the percentage of patients with severe neutropenia (grade 4, absolute neutrophil count <0.5×10⁹ cells/L) and the duration of severe neutropenia, irrespective of G-CSF use.

In August, the FDA granted priority review for trilaciclib to reduce chemotherapy-induced myelosuppression based on these pooled data.

CDK4/6 inhibitors are widely used as anti-tumor agents in hormone receptor-positive breast cancer. While trilaciclib was tested in a phase II study as a myelosuppressive agent in triple-negative breast cancer, the trial missed its primary endpoints, though there was an unexpected signal for a potential survival benefit.

Last Updated October 20, 2020