Toxicities Limit Use of PI3K Inhibitors in CLL

Cyrus M. Khan, MD, a hematologist at the Allegheny Health Network Cancer Institute, discusses the issues with PI3K inhibitor trials in patients with chronic lymphocytic leukemia (CLL) and the potential role of these drugs.

PI3K inhibitors have been in use for approximately 7 years, Khan says, with the first being idelalisib (Zydelig), followed by copanlisib (Aliqopa]), duvelisib (Copiktra), and most recently umbralisib (Ukoniq). However, this class of drugs has undergone scrutiny by the FDA’s Oncologic Drug Advisory Committee despite showing progression-free survival benefit. According to Khan, PI3K inhibitors are associated with pneumonitis, transaminitis, colitis, infections, and other adverse events (AEs). Overall survival (OS) has also been poor compared with comparator arms in clinical trials, leading to warnings about their use and drug withdrawals.

Khan says that a limiting factor on the use of PI3K inhibitors is that they have been used until disease progression or unacceptable toxicity based on previous clinical trials. He suggests a time-limited treatment approach to avoid exposing patients to long-term toxicities may be more successful. Treating patients for 6 to 12 months before switching to a less toxic agent could be a better way to give patients the benefit of these novel therapies safely.

TRANSCRIPTION:

0:08 | We've had PI3K inhibitors since almost as long as the BTK inhibitors have been approved, [which was] 7 years ago or so. The first [PI3K inhibitor was] idelalisib, then copanlisib, then duvelisib, which was oral, copanlisib being the only [intravenous]. Then, more recently, we had umbraslisib come out, but [the developer] withdrew their application, so it's no longer available on the market.

0:34 | The problem with these drugs has been the AE profile. We've had a lot of autoimmune problems come up: pneumonitis, transaminitis, colitis, infectious complications. In some of the studies, the overall survival has even been poor on PI3K inhibitors rather than the standard of care [or] whatever they were being compared to.

0:54 | We use all these novel agents in a fashion where we continue them until progression or toxicity. I think, in the future, if some of these drugs have to come out, probably a more time-limited treatment would be better so we don’t expose the patients to the long-term toxicity of these drugs. We might see in the future, if at all, use it for 6 to 12 months, buy some time until they can go onto other drugs or clinical trials or cytoreduce them, or something of that sort, but I think continuous use has been a problem with the PI3K inhibitors.