Dr. Kahl on Differences in Mechanisms of Action of PI3K Inhibitors in Follicular Lymphoma

Brad S. Kahl, MD, medical oncologist, Siteman Cancer Center, professor of medicine, Division of Oncology, Washington University School of Medicine in St. Louis, discusses the differences between mechanisms of action of PI3K inhibitors in follicular lymphoma.

PI3K inhibitors must target the delta isoform of PI3K to yield efficacy and kill lymphoma cells, says Kahl. However, the FDA-approved PI3K inhibitors target other isoforms, in addition to targeting the delta isoform, to varying degrees, Kahl explains.

For example, duvelisib (Copiktra) hits the gamma isoform of PI3K, which could explain why the agent confers an increased risk of pneumonitis, colitis, and opportunistic infections, says Kahl. Compared with the other 3 approved PI3K inhibitors, duvelisib is most effective at killing T cells, so the agent may have utility in treating patients with T-cell lymphoma, Kahl says.

Additionally, copanlisib (Aliqopa) hits the alpha isoform of PI3K, which could account for any hyperglycemia observed with the agent, Kahl says. Umbralisib (Ukoniq) appears to target the gamma, alpha, and beta isoforms less than other agents, which could contribute to its slightly improved safety profile, Kahl explains. Ultimately, the subtle differences in targeting non-delta isoforms can yield clinically significant differences in the safety profiles of PI3K inhibitors, concludes Kahl.