Renata Ferrarotto, MD, discusses trilaciclib’s unique mechanism of action in small cell lung cancer and the data that led to its FDA designation.
Trilaciclib administered prior to chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC) helped to reduce chemotherapy-induced myelosuppression and limit the need for granulocyte colony-stimulating factors (G-CSF), erythropoiesis-stimulating agents (ESA), and blood transfusions, explained Renata Ferrarotto, MD.
In pooled results of 3 double-blind, placebo-controlled clinical trials, 242 patients with ES-SCLC were randomized to receive trilaciclib (n = 123) or placebo (n = 119) prior to chemotherapy.1 Results showed that 13.6% of patients on placebo were hospitalized due to chemotherapy-induced myelosuppression or sepsis vs 4.1% of patients on trilaciclib. Moreover, the incidences of hospitalizations due to chemotherapy-induced myelosuppression or sepsis per 100 cycles were 5.7 in the placebo arm and 0.94 in the trilaciclib arm.
These findings combined with the reduced need for supportive care imply that this agent may be able to improve quality of life for patients with this disease, Ferrarotto explained.
“By preventing chemotherapy-induced myelosuppression and reducing the need for supportive care and interventions, trilaciclib has the potential to improve the quality of life for patients with SCLC receiving myelosuppressive chemotherapy,” she said.
The FDA recently granted a priority review designation to a new drug application for trilaciclib for patients with SCLC who are being treated with chemotherapy.2 The application was based on the collective findings from the above-mentioned studies.
In an interview with OncLive, Ferrarotto, an associate professor of the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, discussed trilaciclib’s unique mechanism of action and the data that led to its FDA designation.
Ferrarotto: We know that chemotherapy can damage hematopoietic stem and progenitor cells (HSPCs), which leads to myelosuppression. This is one of the most common dose-limiting toxicities from chemotherapy and can significantly impact a patient's quality of life, [as well as] potentially impacting treatment outcomes [because of] dose reductions or delays. Now the interventions that we have to mitigate myelosuppression are the use of G-CSFs, ESAs, or blood transfusions. They're specific to individual cell lineages and are given reactively to patients [showing signs] of myelosuppression.
Trilaciclib is a CDK4/6 inhibitor that has a very short half-life and is administered prior to chemotherapy when chemotherapy is given. What it does is that it arrests HSPCs, which are dependent on CDK4/6 for proliferation. By arresting them in G1, trilaciclib reduces the chemotherapy-induced myelosuppression. That leads to preservation of the immune cells and can [also] enhance immune response. It's also [used in] small cell lung cancer specifically, which is a CDK4/6-independent tumor due to retinoblastoma loss. The rationale is to use a CDK4/6 inhibitor with a short half-life right before chemotherapy, so we can arrest the HSPCs in G1 without interfering with the tumor cells that continue to proliferate because they are CDK4/6 independent and, thereby, protects the HSPCs from the damage of chemotherapy.
One of the unique things about trilaciclib is that it protects all lineages; you give it preventatively, not reactively in order to protect HSPCs during chemotherapy. These are some of the advantages of this agent in comparison with G-CSF or blood transfusion.
There were 3 placebo-controlled randomized trials with trilaciclib prior to chemotherapy in patients with metastatic SCLC [presented at the meeting]. We pooled the data from the 3 analyses, so we would have a higher statistical power to show the myelopreservation effects of trilaciclib.
Across the 3 studies, 123 patients received trilaciclib prior to chemotherapy and 119 received placebo. What we saw is that trilaciclib prior to chemotherapy significantly decreased induced myelosuppression and the need for supportive care interventions. [We observed a] 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-CSF, blood cell transfusions, and ESAs.
There was also a sixfold reduction in the incidence of hospitalizations due to chemotherapy-induced myelosuppression or sepsis in patients who received trilaciclib versus placebo. 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. That's a significant reduction in the number of hospitalizations.
These data are particularly pertinent right now considering the current health care, [COVID-19–centric] environment where we have limited resources, infection [risk], and the need to minimize patients' exposure and hospitalization.
The company G1 Therapeutics, Inc. has submitted a new drug application to the FDA. The application has priority review and the [Prescription Drug User Fee Act] action date is February 15, 2021.
There are also thoughts to study trilaciclib more in the definitive setting for patients with SCLC who are undergoing radiation therapy. Beyond lung cancer, they are actually studying trilaciclib in triple negative breast cancer with some promising results that will be presented at the 2020 San Antonio Breast Cancer Symposium. There is also an ongoing Phase 3 study in colorectal cancer with myelopreservation primary endpoints. These are very exciting data and we're all looking forward to seeing what the FDA determination is going to be in a few months. [The agent] may soon become available to patients with SCLC.
What is really also of interest and is an area of research is to see how the preservation of the immune cells will impact the response to future lines of therapy, such as immunotherapy or even other targeted therapy or cytotoxic chemotherapy knowing how important the immune system is in response to therapy.