Use of PI3K Inhibitors in Relapsed Follicular Lymphoma

We now have multiple different PI3-kinase inhibitors that are approved with treatment of 2 relapses or, excuse me, 2 prior therapies in follicular lymphoma. So there’s idelalisib, there’s duvelisib, and there’s copanlisib, each a little bit different. We know that idelalisib was the first in class. It targets the delta isoform, which seems lineage restricted to lymphocytes. Copanlisib targets both the delta and the alpha isoform. Maybe that’s important in terms of mechanisms of escape, having a little bit broader activity—duvelisib, targeting yet another delta plus gamma, gamma thought to work on the microenvironment. Maybe it increases the efficacy. Maybe it broadens the spectrum of diseases that can be controlled.

Let’s talk about copanlisib first. So, copanlisib was first approved for the treatment, just recently approved for the treatment of 2-prior-therapy follicular lymphoma. Scott, what are the data there, and how are you using this?

Yeah, so copanlisib was approved based off a phase II study, based on overall response rate, accelerated approval. And it’s a unique mechanism. It’s alpha/delta. Alpha is an important isoform in the insulin pathway, and so we see some off-/on-target adverse effects being hyperglycemia along with hypertension. It’s given IV [intravenously]; so, unlike the oral continuous, it’s given IV, typically 3 weeks on, 1 week off, and the overall response rate was about 60%. The majority of patients were follicular. There was a component of marginal zone, as well, in that population. It does seem like the efficacy is right around what we would expect for the other. I don’t think one is that much stronger in terms of efficacy data. The duration of response is very similar, around…a year.

If you actually looked, the number of cycles was a little bit shorter with copanlisib, so there are about 6 months of treatment. And so it has its own unique pros and cons, and it’s great to have 3 potential options. It’s certainly, like Nathan said, in the majority of people that are getting PI3K, those early relapsers, for whom I’m looking at it as a bridge. They’re not going to be on this for years. This is really how do I get them in a better place for clinical trial, whether it’s me bringing CAR [chimeric antigen receptor] T for these patients. And so it’s an important tool in our toolbox, but it’s unlikely to change up-front therapy and that sort of thing.

Ian W. Flinn, MD, PhD: Right. It might be a ways before we can figure out how to give this in frontline. But it does look like it works relatively equally, so for all the different risk groups you can think of. And then the CHRONOS-1 study was in a double-refractory patient population. But, when you look at those groups, it seems similar?

Right, I think it’s overall similar. I mean, numerically, the response rate might be a few points higher, but the duvelisib and idelalisib was a double-refractory, as you say. Copanlisib was simply a 2-prior, so probably a little less heavily pretreated, population, but had really very comparable results and, I think, an overall comparable adverse effect profile. Maybe hypertension, hyperglycemia is obviously more prominent, targeting the alpha isoform; diarrhea, maybe a little less. But the overall net adverse effect profile is pretty comparable.

Ian W. Flinn, MD, PhD: Right. They’re pretty transitory, the hyperglycemia and the hypertension tension, although maybe it would be a concern in someone who already has those issues. I’m taken by the alpha isoform. I’m not so sure that follicular lymphoma is the disease for which inhibiting the alpha isoform is the most—makes the most difference. Maybe in mantle cell—we have…laboratory data at least that show us that in mantle cell lymphoma, there’s an escape mechanism through the alpha isoform. You know, we talked earlier about IV versus [subcutaneous] rituximab. Now we have an IV PI3-kinase inhibitor. What do you think about that?

So, patients in general that have lymphoma are used to getting IV therapy. I think the oral is clearly the more convenient. Again, it sometimes depends on the acuity of the situation. In patients who really need to get out of trouble, I think that IV therapy—and this is given weekly with a week off—is not a big issue. The issue, I think, comes when you’re putting patients on extended dosing, and we’re getting patients who are in remission. No one wants to go to the doctor’s office once a week and get an IV infusion. And, clearly, in that setting, an oral drug is probably more beneficial or, sorry, easier to deliver.

But, in the short term, I think in patients who again are on the third line of therapy, I think if you get an effective regimen and the adverse effect profile is not too tough, IV—you can deliver IV without a problem. The problem is when you start to get into these kind of extended dosing patterns. Then I think the delivery starts to become more relevant.

Ian W. Flinn, MD, PhD: Yeah. So I guess the new kid on the block is duvelisib. So duvelisib, as I mentioned earlier, is an inhibitor of the delta and gamma isoform. It is an oral drug. And like idelalisib, it was tested in a double-refractory patient population, meaning patients that were refractory to both chemotherapy and rituximab. And so I think it had relatively similar adverse event profiles that we’ve seen with the other class of drugs. It’s not clear, I think, from that study alone, at least, whether inhibiting the gamma isoform changes things. I think the thing that’s interesting to me at least is that with duvelisib and inhibiting the gamma isoform, that maybe there are data that show you can treat T-cell lymphomas and other diseases, so maybe it will make an important contribution there. It’s now, of course, approved for the patients like the others with 2 prior lines of therapy—so a lot of treatment options for this patient population.

Transcript Edited for Clarity