The rationale for using CDK4/6 inhibitors to prevent myelosuppression in patients receiving chemotherapy-containing regimens for extensive-stage small cell lung cancer.
Charu Aggarwal, MD, MPH: Chemotherapy in combination with immunotherapy is the standard of care for management of patients with extensive-stage small cell lung cancer. We now have not 1 but 2 immunotherapy agents, including atezolizumab and durvalumab, that are approved and administered with a platinum-based etoposide combination doublet. The chemotherapy portion of it works by unfortunately indiscriminately killing proliferative cells, which may include immune cells. Therefore, the hypothesis is that the full benefit of the combination chemotherapy-immunotherapy combination may not be realized because of the resulting myelosuppression.
The idea that an intervention that prevents chemotherapy-induced myelosuppression and thereby maintaining immune system function could therefore reduce the adverse events, or adverse consequences of chemotherapy, and potentially augment the antitumor efficacy of these chemoimmunotherapy agents by maintaining the immune milieu and maintaining the myeloid progenitor cells and protecting the proliferating cells.
Trilaciclib is a first-in-class myelo-preserving therapy that is being evaluated or has been evaluated in several trials to prevent chemotherapy-induced myelosuppression, especially in adult patients with extensive-stage small cell lung cancer. The way that it works is by transiently arresting the CDK4/6-dependent cells in the G1 phase. It can prevent them from proliferating in the presence of cytotoxic chemotherapy, and therefore it can provide resistance to chemotherapy-induced damage and maybe even favorably alter the tumor-immune microenvironment through this transient T-cell inhibition and have some differential effect on T-cell subsets. There have been a few studies in which trilaciclib has been administered before chemotherapy, resulting in preservation of the cell lines with no significant impact on the chemoimmunotherapy. This offers a promising approach in the future.
Jared Weiss, MD: Normal healthy cells in the body, including those in the bone marrow, are dependent on CDK4/6 to move from G1 to S phase of the cell cycle. That’s a normal healthy cell function. In contrast, some cancers such as small cell are Rb null and, therefore, not dependent on CDK4/6 to progress. A drug like trilaciclib is an IV [intravenous] short-acting CDK4/6 inhibitor, and it holds the bone marrow progenitors and theoretically potentially other cells out of the cell cycle while the chemotherapy is washing by it. Chemotherapy of course is a poison, but it’s a selective poison in that it poisons cells while they’re dividing. The idea is that you stop the bone marrow progenitors from progressing into the cell cycle; they’re protected against chemotherapy. Small cell was the first cancer in which this was studied because you would not hypothesize or expect any effect for better or for worse on the cancer itself. Any effect seen would be purely on myelo-protection, and there wouldn’t be potential clinical benefit or harm from action of the CDK4/6 inhibitor on tumor cells.
Transcript edited for clarity.