Clinical Trials with Early PI3K Inhibitors in R/R FL and MZL


Expert hematologist/oncologists discuss the use of early PI3K inhibitors in the management of R/R follicular lymphoma (FL) and MZL (marginal zone lymphoma).

Jason M. Melear, MD: A good place to start would be with the agents that have been out for some time and have already been approved. Idelalisib is, of course, the initial 1 we discussed. Duvelisib and copanlisib have also been approved for follicular lymphoma in the last couple of years. You are involved in the trials for a lot of these agents. What’s your general thought process? Maybe we can go through the data of these trials and look at those 3 agents and what got them approved or their follow-up process. We could probably start with idelalisib, the first agent; we have had that agent for over 6 or 7 years. That was a PI3K delta inhibitor that came out several years ago for follicular lymphomas and CLL [chronic lymphocytic leukemia].

Ian W. Flinn, MD, PhD: Idelalisib was an exciting drug to work on. It was the first in its class. As I said, it inhibits the delta isoforms. We were specifically working with the hypothesis that we’re not getting the off-target toxicities. We will talk about it in a little bit. If you inhibit the alpha isoform, you can get problems with glucose metabolism and high blood sugars. Perhaps, when inhibiting the gamma isoform, you will run into problems with T-cell function. The thought of purely inhibiting the delta isoform was of great interest. That entered into a phase 1 clinical trial; I remember doing the original phase 1 trial with that drug. Even at the lowest doses, we saw efficacy across an array of lymphoid malignancies and B-cell malignancies. That was quite exciting, but in the mouse models that were done prior to the development of any of these drugs, the knockout model showed that there’s a problem with autoimmunity. The mice who have a G knockout of the delta isoform of the PI3K develop a colitis, and that was seen with idelalisib. 

Thankfully, such effects do not occur until patients have been on the drug for a while. Usually a late event occurs, but you can get an autoimmune colitis with that. It may often need the same therapies that treat an inflammatory bowel disease, such as oral steroids and things like that. A lot of times, it goes away if you pause the drug. Still, it was an important finding. The other issue we found, early in the development of idelalisib, was a hepatitis that occurred. Patients had an increase in their transaminitis. That was usually very early on, somewhere between 2 and 10 weeks; patients could get an increase in their LFTs [liver function tests]. The good thing is that, while that issue needs to be dealt with by the doctor, the patients did not know that was going on. They did not feel bad with it. You held the drug and you could get the LFTs to calm down. You could usually restart the drug without a lot of difficulty, so that could be overcome.

The bigger issue is the later events that happened with the colitis. That ultimately went into a pivotal phase 2 trial that showed that you can get durable remissions. Approximately half the patients will respond; perhaps a little more than half the patients will respond. You can get durable remissions and progression-free survival for about a year. The long-term fall from that study continues to show that. That is an important part of our armamentarium. I’m curious, Jason, have you used idelalisib? What’s your experience with it?

Jason M. Melear, MD: My experience was pretty good with idelalisib. We had it in trials and even back in the CAL-101 days. We had patients who had multiple treatments go into nice remission with that agent. There was no question about it. It was a very exciting agent, but as you stated, the biggest issue was colitis, which could be significant. Some patients experienced multiple stools a day; we had to put them on steroids. It’s an agent that I had been using until recently. We had some familiarity with it. Certainly, we cannot have issues with the patients, especially since colitis could come on months down the road after they’re doing quite well. With G-abnormalities, as you’ve said, usually the patients don’t know about it: You discontinue it; it gets better. It’s not usually a huge issue. We did see some issues with infections, especially with hepatitis C and hepatitis B reactivations. We especially had it in some early line studies. In the first-line studies, 1 thing that came out of those 2 was it seemed like patients may even do worse the earlier you put it in, because they may experience more issues with immunosuppression, autoimmunity, and more LFT abnormalities. Those trials didn’t get approval there with combinations up front. But overall, it’s something I have been using for patients with multiple relapses, and they have had some really good responses to it.

Ian W. Flinn, MD, PhD: It was a unique finding, the concept that the earlier in the line of therapy that idelalisib was used, you would sometimes get more events. It’s almost a more incompetent immune system. There were problems with that. Others have looked at why that might be. It looks like it has to do with effects on T-regulatory cells. By deleting T-regulatory cells, you get more immune events. There is this balance between immunity and immunosuppression that’s important with these drugs.

This transcript has been edited for clarity.

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