PI3K Inhibitors for R/R Follicular Lymphoma

Ian Flinn, MD, PhD: I want to talk a little about PI3 kinase inhibitors. As I think most of us all know, there are 3 different PI3 kinase inhibitors that are FDA approved for the treatment of follicular lymphoma. They are idelalisib, copanlisib, and duvelisib. They all vary in regard to the isoforms that they target. As is well known, there are 4 different isoforms of the PI3 kinase: alpha, beta, delta, and gamma.

Idelalisib was first developed and was a specific inhibitor of the delta isoform. The thought was that if we were not hitting these other isoforms, we may not get some of the off-target toxicity that you see by inhibiting the alpha isoform. Then copanlisib came along. It’s different. It’s an IV [intravenous] drug. The other 2 drugs are oral drugs. It’s kind of a pan inhibitor, but it hits mostly the delta isoform as well as the alpha isoform. There are some issues with hyperglycemia and hypertension. These are probably a direct result and are what we would have predicted from the preclinical models. Most recently, duvelisib has been FDA approved for patients treated with 2 prior therapies. This drug is pretty similar, in my mind, to idelalisib. It inhibits both the delta and gamma isoforms. The thought is that by inhibiting the gamma isoform, maybe you’re picking up some of the microenvironment in these cell-cell interactions that promote survival of the neoplastic cell.

But clinically, to me at least, they all seem remarkably similar, although there are differences in the routes of administration. At least the response rates seem similar. Maybe there’s some differentiation based on adverse-event profile. Loretta, you’ve used these drugs. Where are you incorporating them in your practice? Do you differentiate, for 1 patient from the next, which therapy you use?

Loretta J. Nastoupil, MD: Until recently I was using it solidly in third-line setting or later, just because of some of the concerns of a worse toxicity profile in patients who were less heavily pretreated. At least that’s what we saw emerge in CLL [chronic lymphocytic leukemia] as it moved into earlier lines of treatment. I do think that the efficacy looks to be more similar than different across the agents. There probably is some difference in safety profiles—and that’s probably important, particularly with copanlisib—with the hypertension and hyperglycemia. Although it’s transient, and we probably should not overreact to it. For those patients who are borderline diabetic, my concern is that I’m going to make them full-blown diabetics. That’s going to require some more counseling, monitoring, and education. So I might sway away from it in that setting and consider, instead, either idelalisib or duvelisib. The oral versus IV formulation might lead to some differences in the safety profile, but may also lead to some differences in terms of patient preference. If I have an oral therapy, which is easier to administer for a patient who’s not close to my practice, that might be worth considering.

The 1 that’s out there that might change things is umbralisib. This is a PI3 kinase inhibitor. In my experience, this probably has the easiest toxicity profile to manage. That might provide an additional agent that might have more uptake than what we’ve seen with those available so far.

Ian Flinn, MD, PhD: Yeah, umbralisib is an interesting drug. It’s a delta inhibitor, but the thought is it also inhibits CSNK1E. Maybe that is changing the adverse-event profile? We know this from the preclinical models, right? In the mouse models where there was the pure knockout of the delta isoform, the mice got this colitis. We’re certainly seeing that in the clinic as well, so it’s predictable. At least umbralisib doesn’t have some of the hepatotoxicity that is seen with both duvelisib and idelalisib.

Krish, you’ve used all these drugs. What is your approach? Do you see the same adverse events, and do you see the same efficacy that we saw in the clinical trials?

Krish Patel, MD: My experience probably parallels what Loretta described previously. I am using this therapy largely in third-line setting or later. Often we’re trying to get a patient to a complex therapy, like an allotransplant or CAR [chimeric antigen receptor] T-cell therapy, or on a clinical trial. These are very active agents that can help bridge those patients to those types of therapies. In general, yes, the toxicities look quite similar to what was seen in the trials. There have been some interesting perspectives on things like intermittent dosing. We’ve been able to put patients on that trial and see that there may be some differences in toxicity profile in patients who are not getting continuous inhibition vs intermittent. This is a class of agents that has a very important use, but we’re still trying to figure out how to best use these agents.

Ian Flinn, MD, PhD: It’s amazing, isn’t it? We’ve had them for this long, but we still don’t know how to use them properly. The copanlisib data were interesting and gave way to a lot of that, because it is given intermittently, intravenously. Maybe that’s why it has less GI [gastrointestinal] toxicity?

Caron, let’s say you have a patient on idelalisib. We know that this is associated with a couple of adverse events, such as hepatotoxicity, diarrhea, and in some patients, colitis. What’s the best way to mitigate that, prevent that, and successfully keep people on therapy for as long as possible?

Caron A. Jacobson, MD, MMSc: Other than the fact that dosing this in later lines of therapy seems to lead to a decreased incidence of some of these really autoreactive or autoimmune toxicities, I’m not sure of any way to mitigate or prevent them from happening. However, there are things you can do once they start. Obviously, with severe-grade toxicity, you would hold the drug and sometimes even initiate steroids to lead to a clinical improvement. There are cases where patients get low-level enteritis, grade 1 diarrhea, or colitis. In those cases, sometimes you can actually, at least with idelalisib, dose reduce to 50% of the dose. Sometimes patients will improve on that and tolerate it without recurrent colitis. I have done that a couple of times. I have also taken a brief pause and then reinitiated therapy at a lower dose. I have been able to get people through for sometimes even a year or more of therapy without seeing the toxicities recur. It’s 1 way to dance around it but not necessarily mitigate it.

Ian Flinn, MD, PhD: Right. You bring up the reduced dose. I’ve often wondered whether we even know what the right dose is. In the original phase 1 trial with idelalisib, I had patients on that for years and years. However, they were never on the full dose. Maybe they had had an adverse event and we dose reduced, or maybe they were just started at a lower dose and we never found the need to dose escalate. I think there are still a lot of questions out there about how to best use these drugs.

Transcript Edited for Clarity