Follicular Lymphoma: Evolving Treatment Landscape - Episode 9

Long-Term Efficacy and Safety of Copanlisib


Ian W. Flinn, MD, PhD: Scott, copanlisib was recently approved by the [FDA] for the treatment of follicular lymphoma. It’s an accelerated approval. It’s based on the CHRONOS-1 study that enrolled patients with 2 prior therapies. It’s a broader trial for all patients with indolent lymphoma. Now, copanlisib is a [PI3K] inhibitor. It blocks both the delta as well as the alpha isoforms of this PI3K. Can you compare and contrast this with perhaps some of the others? Walk us through some of the data we’re seeing. We’re seeing long-term data from this trial here at ASH.

Scott Huntington, MD, MPH, MSc: That’s a good question. So the approval was based off some early phase encouraging overall response rate, around 60% in terms of the overall indolent lymphoma group. The majority of the patients were follicular, and that’s where the label really is, in follicular. In terms of updates at this ASH, there’s about a 2-year follow-up, and I think it’s important primarily from a safety perspective. This drug kind of surprised us when it was FDA approved, based on some encouraging overall response rate. And so to have the 2-year follow-up showing that the safety data really haven’t changed, I think most notably, certainly instances of immune-mediated colitis, hepatitis, and pneumonitis seemed to be lower in this agent compared with others. As a trade-off, you do see more hypertension and hyperglycemia.

The CHRONOS authors also updated some data on those subgroups at this ASH. So in patients with hypertension, it seems that the majority can tolerate this drug quite well. It seems to be transient in terms of the acute hypertension around the infusions. And similarly for the hyperglycemia, in patients who have diabetes, there were about 20 patients on the study who had diabetes, and those, too, seemed to derive some benefit. I think it’s important to note that both the hyperglycemia and the hypertension really occur around the infusion time.

This drug is cleared more quickly in the plasma compared with, kind of, the tumor microenvironment. And so as an alpha-based toxicity, it’s really around the infusion, lasting around 24 to maybe 48 hours in general—the hyperglycemia and hypertension. And the trial did not really institute specific management. So I think it’s uncertain in the community exactly how we should be managing these folks, and I think it will be encouraging to have more data about how we manage patients with diabetes with copanlisib. Yes, it can be safe, but are there some guidelines for that?

Ian W. Flinn, MD, PhD: Yeah. Ajay, let’s talk about the adverse events profile. It does seem to be different. There are many who have hypothesized that clearly the hyperglycemia and maybe the hypertension have to do with hitting the alpha isoform. But that’s on the bad side. But on the good side, there are lots of some of these immune-mediated issues. Do you think that’s (a) the root of administration, (b) the schedule, or (c) that you’re hitting more than 1 isoform? Other than hand waving, any data here? What do you think?

Ajay K. Gopal, MD, FACP: I don’t think we have any data. I think it’s probably some degree of all the above. The intermittent schedule probably makes a difference but likely the isoforms as well. I think it offers an option to patients, and I think it’s nice to have now 3 choices in this class of drugs. But I don’t think we really understand the why.

Ian W. Flinn, MD, PhD: I mean there are other companies now trying to perhaps explore this and see whether they can duplicate it. But not having constant signal hitting the delta isoform may decrease. The preclinical models for all of this showed that by strongly inhibiting the delta isoform to these knock-in, knockout models, certainly you get the colitis and some of these other autoimmune events.

Ajay K. Gopal, MD, FACP: I think as other trials are being done, we’re learning from prior experience in terms of how to optimally design them. So I think we’ll probably have different dosing schedules in the long run for the oral agents too.

Ian W. Flinn, MD, PhD: Nathan, what about IV [intravenous]? What about the IV administration? We talked earlier about IV rituximab and IV and then subcutaneous. You could probably imagine the circumstances where that would be good. You could imagine circumstances where that may be bad to use. What do you think?

Nathan H. Fowler, MD: Yeah, it’s hard to know. I mean, as Ajay poited out, we’re still learning about some of the reasons why patients develop toxicity. And there’s a hypothesis that if these drugs are not passing through the gut, then this is the reason they don’t have colitis. Again, I don’t really know whether it’s the IV versus the oral. I think with IV and oral, not to be simplistic, it’s delivery, right? So I think most patients, if I were a patient, I would probably rather have a pill than IV. When the disease is significant, I think IV is not so much of an issue. Again, it’s all about risk and benefit, right? If I’m worried about the disease and the disease is threatening, patients are very used to getting IV treatments, whether that’s rituximab or chemotherapy on a regular basis.

The bigger issue comes when you come into extended dosing, especially for patients who are in a remission. Then I think it is because it does become a little more problematic to continue to deliver IV because it requires a visit to the doctor’s office. And many patients don’t like to go see their doctor every week. But I think that we will kind of figure these things out over time, and as Ajay mentioned, there are potentially different dosing schedules that will be used in patients who receive long-term copanlisib, and maybe we’ll see changes in the frequency of dosing. It’s a long answer to your short question. I think it’s easier for patients to get oral, but if you’ve got a more effective drug that’s less toxic and it’s IV, I’m willing to do that, at least in a short term to control a patient’s disease.

Ian W. Flinn, MD, PhD: Great.

Ajay K. Gopal, MD, FACP: Sometimes there are co-pay factors as well. For some patients, they prefer not having it if they’re caught kind of in the middle in terms of co-pay for an oral agent; they’ll prefer the IV. So I think this just comes back toward the theme of individualization, not just the medical side but the patient’s interests.

Ian W. Flinn, MD, PhD: You bring up very important issues. It’s very frustrating in things that I guess we feel like shouldn’t weigh in but do

Transcript Edited for Clarity