Considering the Value of PI3 Kinase Inhibitors in FL
Insights From: Bruce Cheson, MD, Lombardi Comprehensive Cancer Center; Anas Younes, MD, Memorial Sloan Kettering Cancer Center
Anas Younes, MD: The PI3 kinase pathway is an oncogenic pathway frequently activated in a variety of cancers, including lymphomas, but it’s also activated in lung cancer, breast cancer, and other malignancies. So, it’s a dominant oncogenic pathway, and that’s why people are interested in targeting multiple types of cancers with it, including lymphoid malignancies. It’s a complicated pathway, because at the top of the pathway there are multiple PI3 kinase isoforms. Any of them can activate downstream events in this pathway, and frequently, multiple isoforms can work together in activating the path. So, if you inhibit one, the other one may compensate for it, and so forth. But in general, it’s a pathway that is oncogenic, and if you inhibit this pathway, you can induce either cell sacrifice—where you can inhibit the proliferation—or cell death.
Bruce Cheson, MD: Idelalisib is the first PI3 kinase inhibitor to be approved by the FDA for hematologic malignancies. It was approved on the basis of a study published by Dr. Gopal, a single-arm study where the response rate was around 60% with a few complete remissions, and the median progression-free survival was around 11 to 12 months. So, this pill, which you take twice a day, induced responses in a majority of patients, and these were clinically meaningful. And as a result, the drug was approved and has been used in the treatment of follicular and low-grade lymphomas as well as in CLL.
Anas Younes, MD: The first PI3 kinase inhibitor approved by the FDA is idelalisib, which is an oral PI3 kinase delta selective inhibitor, approved for both CLL and follicular lymphoma. And at least in follicular lymphoma, the response rate is about 54% or 55%—pretty good, especially in patients who failed 2 prior regimens. So, it’s a good response rate and lasts for about a year or so. Just because they are not chemotherapy-based targeted therapies that doesn’t mean they don’t have side effects. They do have side effects that are unique for this class of agents. In general, the PI3 kinase delta inhibitor, idelalisib, is relatively safe, but there are approximately 10% or so side effects that will lead to dose interruption or reductions.
What we worry about are colitis, hepatitis, and pneumonitis, so mainly autoimmune mediators. You can have lung infiltrate that is not infectious that requires dose interruption, and maybe steroids. With colitis, you have frequent diarrhea and then the hepatitis or transaminitis. You have an elevation of liver function enzymes that requires dose interruption and reductions. Colitis is very difficult to predict, but for patients with autoimmune disease, especially with celiac and Crohn’s disease, you would want to avoid this in these patients.