Safety and Efficacy of PI3K Inhibitors in MZL and FL

Anthony Mato, MD, MSCE: I want to delve into another topic that is near and dear to my heart, even in the CLL [chronic lymphocytic leukemia] world, which is PI3K inhibitors. I always have a lot to say. While we have a couple of agents approved in CLL, we now have 4 agents approved in follicular lymphoma [FL]: copanlisib, duvelisib, idelalisib, and umbralisib. Are there any that I forgot?

Lori A. Leslie, MD: That’s it to my knowledge.

Anthony Mato, MD, MSCE: We probably don’t need to spend a lot of time delving into the disease biology, except to say that PI3K seems to be an appropriate target across all B-cell lymphomas at this time. Let’s talk about the individual agents in reverse order. Idelalisib was the first to be approved for these indolent B-cell lymphomas. What are your thoughts about the data and long-term follow-up for idelalisib? What are your thoughts about this as an appropriate therapy for FL and marginal zone lymphoma? What line are you thinking about using this agent? Maybe we can lump that and duvelisib together.

Lori A. Leslie, MD: PI3K is a very active target in follicular and marginal zone lymphoma that is probably underutilized because people had tough cases with toxicity. They have a bad rap overall because of the toxicity profile. We have the 2 oral therapies: idelalisib and duvelisib. Both are taken twice daily and approved for third line or later in follicular lymphoma. In those studies, patients had 3 or 4 prior lines of therapy. Overall response is somewhere in the 50% to 60% range. Most patients have a partial remission. There are another 30% or so of patients who have stable disease. So it contained a clinical benefit ratio up to around 80%, but the duration tends to be somewhere around a year or a little less. My general feeling with PI3K is that it’s maybe a bridge to something else. It’s not really a longer-term therapy. A handful of patients can stay on it longer term, but in my practice, toxicity or progression has usually happened around the 1-year point. Do you have a similar experience?

Anthony Mato, MD, MSCE: I do. The target is appropriate, but the major limitation of these drugs is the adverse event [AE] profile that leads to early discontinuations. That has been a theme throughout their development in CLL and B-cell lymphomas. I’ll briefly mention the toxicities. Infections, opportunistic infections requiring prophylaxis, pneumonitis, transaminitis, and colitis are what jump out at me as the things we need to worry about. All of them are immunological effects of these drugs, causing autoimmune phenomena. That’s probably the best way to describe it when you think about the lung, liver, and GI [gastrointestinal] toxicities, but paradoxically, also causing immunosuppression to the extent where people are getting opportunistic infections. This is a drug class, more so than any of them that we’ve mentioned so far, where expertise in managing adverse events can lead to successful patient outcomes and limit the risk of death. Are there any AEs associated with these drugs that I missed, and we should think about? We should probably mention copanlisib because of the alpha effects. Do you have any thoughts there? Are you seeing any toxicities that are worth mentioning?

Lori A. Leslie, MD: Yes. Copanlisib is a different type of approach. It’s an IV [intravenous] medication rather than oral. Patients have to come weekly for 3 weeks and then get a week off, which some patients love, while others do not like at all. The toxicity profile, as you mentioned, is different. You certainly can see some of those immune-mediated toxicities, but the more prominent toxicities are metabolic. We’ve got the infusion-related hyperglycemia and infusion-related hypertension. That typically is just while the patient is getting the treatment. We can manage that, and it’s not something that would make me shy away from using copanlisib. The few times I’ve used it, the other immune-mediated toxicities that you would have with an oral agent were maybe slightly less prominent, at least in part because you’re bypassing the oral route with the IV administration.

Transcript Edited for Clarity