The Role of PI3K Inhibitors in Relapsed/Refractory FL and MZL - Episode 5

Role of Umbralisib in R/R FL and MZL

Ian W. Flinn, MD, PhD, and Jason M. Melear, MD, review the tolerability and efficacy of umbralisib in the management of R/R FL and MZL.

Ian W. Flinn, MD, PhD: The new kid on the block is umbralisib, which has a differentiating safety profile. We know that it’s an oral agent. It’s both a PI3K delta inhibitor and a CK1 epsilon inhibitor. We have all become really used to, and understand, the pathway with a PI3K. CK1 epsilon is a little less well known. It is a lesser-known kinase. It looks like it inhibits—it is important in a lot of the cell cycle events. It can cause the proliferation or survival of many different cells, including malignant cells. It also has a secondary effect that has to do with our immune system. In laboratory systems, looks like it protects T-regulatory cells from the insults of PI3K inhibition. That may be an explanation. This may be a way we could decrease some of the autoimmune events that occur, as we just discussed. Umbralisib inhibits both of these. Jason, have you used umbralisib? What has been your experience?

Jason M. Melear, MD: We have had it in trial here for several years. In my experience, it has been better tolerated in general than the idelalisib we have used for several years. I certainly think the colitis seems to be much less common. Diarrhea is still common. I think the trial was just recently released. Still, over 50% of people get diarrhea of some sort, but it’s usually grade 1 and 2: a couple of stools, a couple of soft stools. There’s not nearly the same incidence of 10-plus watery stools, although it does occur. The actual colitis rate in the trial was only 2%, but grade 3 diarrhea rate was a little less than 10%. It has certainly been, in my experience, much more tolerable in that way. The responses, from what I have seen, seem to be comparable with the other PI3 kinases when I’ve seen those used.

The duration seems comparable, just in the patients I have seen. We have not really had a lot of issues with any type of opportunistic infections, but of course we do use prophylaxes for our patients; I usually use Bactrim [sulfamethoxazole and trimethoprim], Dexone [dexamethasone]—1 of the 2 for treating Cystitis while I watch for CMV [cytomegalovirus]. I haven’t had any problems with that in this case. There are reported cases of some rashes and things like that, but I really have not seen it that much. I’ve seen some LFT [liver function test] abnormalities, but it doesn’t seem to be significant. We have been able to put those patients back on this treatment, but in the trial, you will see a 7% or 8% chance of the grade 3 where you would just take them off as we talked about before. You can try to restart your patient on the regimen and, if you need to, dose reduce them by a pill and go from there. To this point, my experience has been that it has been tolerable and we have been pleasantly surprised in that regard with this agent. Have you been able to use it at all?

Ian W. Flinn, MD, PhD: Yes, we have done a number of trials with it. From phase 1 onward, we have done a number of trials with them, and I have a very similar feeling. Early on in the trial we were doing, 1 of the first abstracts came out and said, “There are no great or very few LFT abnormalities.” I said, “Really? That’s hard to believe. It is a class effect.” We were going back through every patient and looking at every patient’s LFT abnormalities; they did not have them. To me, that’s definitely a differentiating effect of this drug compared with the other PI3 kinase inhibitors, particularly the oral inhibitors. As for colitis, it’s often difficult to distinguish what’s colitis vs what is grade 3 diarrhea. A lot of times people are not getting scoped; this is semantics. That said, I agree with you, and the incidence is significantly less than what’s seen with the other drugs. Overall, this is an easier to use PI3 kinase inhibitor. It still has some of these adverse effects [AEs]—you still have to watch for them—but the incidence of this AE is a lot less. The efficacy is similar to what we’re seeing with the others, given the different trials. In different time periods and with different, prior therapies that these patients have had, it’s relatively similar.

This transcript has been edited for clarity.