Role of PI3K Inhibitors in the Management of R/R FL and MZL


Ian W. Flinn, MD, PhD, and Jason M. Melear, MD, review clinical trial data for idelalisib, copanlisib, and duvelisib and discuss their personal experience using these agents for the management of R/R FL and MZL.

Jason M. Melear, MD: I know you’ve been involved with duvelisib. I know you’re an author on papers on the topic. How do you think that compares with idelalisib? It’s also a PI3K delta inhibitor, correct?

Ian W. Flinn, MD, PhD: Absolutely. It’s a PI3K delta inhibitor. It inhibits not only the delta isoform but the gamma isoform. Here, the hypothesis that I was talking about earlier—that perhaps by inhibiting the gamma isoform, you’re having an effect on the microenvironment and the cell-cell interactions that promote survival of the cells—comes into play. All these things sound great in the laboratory, but how they translate into the clinic is less clear. In my mind, duvelisib is an improvement over idelalisib, although there aren’t radical differences. I am not 100% sure whether that we know how to use these drugs better than we used to, but perhaps there’s a mildly improved safety profile.

The efficacy, in my mind, of almost all these drugs—we’ll go through them—is that they are almost all similar when it comes to efficacy. They differentiate themselves when it comes to their adverse-events [AEs] profile. With duvelisib, we also see the LFT [liver function test] abnormalities that you can get with idelalisib. You can also see the colitis; both seem a little better than what you get with idelalisib. You also have to be aware they’re not studied; they were not tried in the same study. Maybe different patient populations led to some of these differences. They’re very similar drugs in that manner.

Jason M. Melear, MD: They’re both oral agents, of course. They’re used in similar fashions: orally, daily, to progression. I have not used duvelisib. I have for many years used idelalisib and umbralisib—which we’ll talk about later—in trials. I’ve also used some other phase 1 PI3Ks, which we won’t talk about today, in trials. I tended to use all those, and I haven’t used too much of the duvelisib or the IV [intravenous] PI3K inhibitor copanlisib, which is also a little different. It has some alpha effects to it, so it can cause a bit of a different adverse-effect profile. You can have some sugar abnormalities, like high blood sugars, with that 1.

My understanding is that there isn’t as much colitis for patients. Still, some colitis is present. There are more blood sugar issues. The effectiveness, as you mentioned, is roughly the same. The response rate is about half for these patients who relapse, and the duration of response on that order is 11 to 12 months. We may see better results for that agent. Maybe we get a duration for a little over a year for that agent. That’s what I have seen in the trial. It looks like the response rate and the duration rate is a little better for copanlisib. It is not a perfectly comparable trial. Do you have the sense that it’s any more effective with the different mechanism of action, or is it more similar in effectiveness?

Ian W. Flinn, MD, PhD: I honestly think there are more. When I look at the agents, and when I pick 1 vs the other, it’s generally not based on its efficacy. But if 1 had a worse adverse-event profile, I would be particularly concerned. That is why I would pick 1.

You mentioned that this is an IV [intravenous] drug. It’s the only 1 of 4 of the FDA-approved PI3-kinase inhibitors that is IV. For my patient population, that’s not a plus, but there are patients who may, for a variety reasons, be better off with an intravenous form of treatment rather than an oral form. It’s a little more cumbersome to do it that way, but it’s nice to have in our armamentarium. It’s good to have 1 that’s an IV that you can go to compared with the others. As you mentioned, it is more of a pan-inhibitor, although it is hitting alpha and delta strongly. I don’t really know if the differences we’re seeing in adverse events from 1 type of drug to the next are because it is IV. Is it because of the schedule that’s being given? It’s not being given continuously. It’s given weekly. That might change some of the adverse events. Or is the selectivity for the different PI3-kinase isoforms the factor to consider?

There are a lot of moving parts to know exactly the cause of the differences we’re seeing. How do you approach it in your practice, Jason, when picking 1 vs the other? You mentioned you had a lot of experience with idelalisib, but there are others too. Is it that you’re just comfortable with idelalisib and you know its adverse-event profile? Is that why you use it?

Jason M. Melear, MD: To be honest, that has a huge bearing on how I tend to use drugs. If there’s a drug that I’m comfortable with, I use that unless it’s a drug that I’ve had such trouble with that I really want to switch our patients off the agent. Certainly, patients have had adverse effects with the idelalisib. But having had multiple trials with it, I’ve gotten used to watching the CNV [cytomegalovirus] and watching the colitis closely, to a point where hopefully I can use it well enough that the patient can avoid any terrible adverse effects where they are sick in the hospital. I tend to be 1 of the people holding on, who has used idelalisib a lot even though others have been approved. Fortunately, I haven’t had other trials of PI3Ks that we can try also.

I don’t feel like I’ve missed out that much by not using the other agents. I’ve had plenty of patients on the P13-kinase inhibitors over the years, and that’s how I’ve used it. I guess I was not moved by the data enough, based on the effectiveness, to change what I was used to. I read it as you did—they seemed pretty similar in their effectiveness, and they just had different AE profiles. I would rather use an oral treatment than IV most of the time, so that wasn’t necessarily a plus. I personally do not like trying to manage my patients’ blood sugars. That was a negative to me.

That is an adverse effect you don’t have in a lot of our agents. You do with steroids. If I can avoid that adverse effect, I would like to. That’s what I’ve done. I’ve used idelalisib, until now, pretty much exclusively. With the newer agent being approved—I know we’re going to talk about this a little later—I might consider going over to that also now that it’s available.

This transcript has been edited for clarity.

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