CDK4/6 Inhibitors and Myelopreservation
EP: 1.Chemotherapy Use & Chemotherapy-Induced Myelosuppression
EP: 2.Management of Chemo-Induced Myelosuppression
EP: 3.Chemotherapy-Induced Myelosuppression & COVID-19
EP: 4.CDK4/6 Inhibitors and Myelopreservation
EP: 5.Analyses of CDK4/6 Inhibitors for Myelopreservation
EP: 6.Chemotherapy-Induced Myelosuppression in SCLC: CDK4/6 Inhibition
EP: 7.CDK4/6 Inhibitors for SCLC: Trials of Interest
EP: 8.CDK4/6 Inhibitors & Myelopreservation in Other Cancers
EP: 9.Reducing the Impact of Chemotherapy-Induced Myelosuppression
Gary H. Lyman, MD, MPH, FASCO, FRCP: One of the more interesting recent developments for reducing the risk of myelosuppression is to utilize inhibitors of CDK4/6. Trilaciclib has recently been accepted for priority review by the FDA. Yesterday, notice came out from the FDA that they had accepted the application for new drug approval for review. While that’s undergoing review, there can be some compassionate access to this agent.
The principle here is that CDK4/6 inhibitors result in the transient arrest of normal cells in the G1 phase of the cell cycle. If given prior to chemotherapy, they may protect stem cells in the bone marrow, as well as the immune system, from chemotherapy damage. Chemotherapy primarily affects the rapidly proliferating cells, both healthy and tumor cells, by inducing this arrest in the in the G1 phase. Prior to giving the chemotherapy, it’s been demonstrated in both animal and human systems that it has the capacity to preserve hematopoietic stem cells, progenitor cells, and committed progenitors.
The trials that have been done based on phase 1 work resulted in a recommended phase 2 dose of trilaciclib. That dose is 240 mg/m2, given intravenously about 30 minutes prior to the chemotherapy. The initial trials have been done in small cell lung cancer with carboplatin and etoposide in 1 of the trials, and with atezolizumab for PD-L1–high patients with small cell lung cancer.
Small cell lung cancer has been used as a prototype or a target tumor for the development of supportive care for cytotoxic chemotherapy. It was used in the original, pivotal work for GCSF. It’s because it’s a rapidly proliferating, high-risk situation in which patients may progress very rapidly. It’s also a situation in which chemotherapy produces responses in a high proportion of patients, but with the ensuant toxicities that we talked about.
These trials, 3 of which were presented to the FDA, were reviewed recently by Jonathan Weiss in Annals of Oncology. As I said, it was previously given breakthrough status, and the new drug application has now been given priority review in patients with small cell lung cancer based on these major trials.
These are pretty exciting and compelling myelopreservation data by a first-in-class new agent. These trials were double-blind, placebo-controlled, randomized trials of either chemotherapy alone or chemotherapy preceded 30 minutes by the trilaciclib. Combined, they clearly demonstrate myelopreservation to a very high degree. Myelopreservation was the efficacy endpoint of these studies. grade 4 neutropenia was reduced from about 50% down to almost 0—I think 2%—across these trials. There was less febrile neutropenia. There was less need for GCSF rescue. Grade 3 to 4 anemia was also reduced. Remember, this is affecting all lineages of the hematopoietic stem cell.
Anemia fell; the risk of grade 3 to 4 anemia fell from 28% in the control group with chemotherapy alone to 19% with the trilaciclib administered prior to chemotherapy. Transfusion was also reduced from 21% to 13% across these trials. The use of erythroid-stimulating agents was cut about in half.
Finally, grade 3 to 4 thrombocytopenia fell from about 40% to nearly 0, with platelet transfusions required in only half as many patients when they received the trilaciclib.
The good news, on top of all this, is that it appeared to have no effect on the antitumor activity of the chemotherapy or immunotherapy. There were no significant or severe adverse effects of concern associated with the trilaciclib.
This is really a win-win. We still need a full FDA approval. We need confirmation in other disease settings beyond small cell lung cancer, and there are other trials being completed in triple-negative breast cancer. There’s an ongoing trial in colorectal cancer. We’re going to have to see how all these data fall out, and whether the effects we see from trilaciclib in small cell lung cancer carry over to other solid tumors and malignancies.
The overall impact of this cannot be overstated. These dramatic reductions in myelosuppression, or the dramatic myelopreservation that’s been seen with trilaciclib in patient surveys, has been shown to significantly delay the deterioration of patient functional status in the symptoms associated with myelosuppression.
We also anticipate, although formal economic analyses are still needed, that there will be a significant reduction in cost and improved quality of life. With less neutropenia and febrile neutropenia, there will be less hospitalization, less need for growth factor support, and fewer transfusion requirements. All this should have a noticeable and significant impact on health care costs associated with supportive care of patients receiving cytotoxic chemotherapy.
Although the data are early and we need more data in other settings, there’s a reason for encouragement and optimism. We now have another strategy for reducing these complications and preserving marrow function across all 3 lineages.
Transcript edited for clarity.
