番茄社区

In the presented at the American Society of Hematology (ASH) annual meeting, patients with relapsed/refractory follicular lymphoma who were treated with parsaclisib -- an investigational, potent, highly selective, next-generation PI3Kδ inhibitor -- demonstrated rapid and durable clinical responses.

番茄社区 brought together three expert leaders in the field -- moderator , , and -- for a virtual roundtable discussion. This final of four exclusive episodes focuses on the results of the CITADEL-203 trial and how parsaclisib measures up with other PI3K inhibitors for follicular lymphoma.

Following is a transcript of their remarks:

Flinn: Hello, I'm Ian Flinn from the Sarah Cannon Research Institute in Nashville, Tennessee. I'm joined today by Loretta Nastoupil from the MD Anderson Cancer Center and Amit Mehta from University of Alabama at Birmingham. We're going to talk about some of the exciting news that's come out at ASH 2021. It was a big year for lymphoma studies this year, and I think we have a great discussion.

We're going to switch now and talk about the CITADEL-203 trial with parsaclisib in patients with follicular lymphoma. I mean, there is now what -- four other PI3 kinase inhibitors that are approved for follicular lymphoma and other forms of B-cell malignancies. What's unique about this drug, and do we need a fifth one? I do think there's some interesting issues about the way the drug was administered in scheduling that maybe can be applied to other PI3 kinase inhibitors as well. What are your thoughts on this drug?

Mehta: So the PI3 kinase inhibitors, they're very active in follicular lymphoma, and that we knew from idelalisib when it was initially approved. But the issue with idelalisib was the side effects -- so diarrhea, colitis, transaminitis, and infection were challenging to begin with. So since then, up until now, there is a constant push to improve on that PI3 kinase. And how it has happened is to make them more specific and highly, highly delta-specific in particular, to see whether we can avoid some of the side effects that we see with idelalisib.

So all the different PI3 kinases, they have a little bit different flavor in their mechanism of action. And that brings a little bit different side effect profile. Parsaclisib especially is a highly specific delta inhibitor, and it was designed specifically to avoid the transaminitis part of the side effect of PI3K-delta.

And actually in the ASH meeting, we had three different settings; three different phase II studies were presented in follicular lymphoma, marginal zone lymphoma, as well as in mantle cell lymphoma. Now mantle cell lymphoma is specific because there is no PI3 kinase approved in the setting and the data were pretty impressive. Same as in marginal cell lymphoma, and follicular lymphoma -- the response rate that I saw was higher, 77% overall response rate, with about 20% complete response rate, which is better compared to other PI3K delta inhibitors.

The side effect profile -- again there were no transaminitis grade four. That's how the drug was designed to avoid that, but diarrhea was still there. About half of the patients had low-grade diarrhea. About 15-16% of patients had high-grade diarrhea and neutropenia.

These were the two grade 3 or more side effects that were seen. But otherwise the agent for parsaclisib was highly active in follicular lymphoma -- from all across the board -- but follicular lymphoma had more activity in that.

Flinn: Loretta, what do you think about the adverse event profile of this and maybe the other PI3 kinase inhibitors? We know from the gene knockout mouse model, that if you knock out the delta isoform, you're going to get colitis at least in the mice.

So is this a fool's errand to try to continue to go out to the same target and think that we're going to have less toxicity with "a cleaner" molecule? I mean, I believe the aminotransferase issue, or should be, as in this study they're also investigating different ways of administering the drug. So, weekly versus daily dropping down the dose. Is that a better approach? I don't think it was 100% productive in this study.

Nastoupil: I think Amit mentioned this at the beginning, that there is activity with PI3 kinase inhibitors, so we're not done yet and we haven't moved past them because of the efficacy. We're just trying to balance the safety. And I agree with you, there are clearly class effects that we have to contend with.

And so I think different dosing strategies are one attempt to try and address that. I think the question about intermittent dosing versus lower dose, once you kind of get to a steady state, in some ways I'm slightly disappointed that we still kind of walk away with daily dosing. But I do think that these newer agents, they probably have to make it a little bit more user friendly for there to be a play in follicular lymphoma.

The efficacy of this agent looks quite striking. So I think just finding that balance will be key.

Flinn: So Amit, just one final question for you. So again, as you mentioned at the beginning, we have multiple PI3 kinase inhibitors, but they're not extensively used because of I think predominantly the adverse event profile that we see in them. Do you think that will change with this drug? Do you think that there will be greater use because of its efficacy and combination with its adverse events?

Mehta: There is a potential, and I always say that any drug has a side effect and you have to learn to identify it early and treat it effectively. Only then will it be effective. So I think from the field perspective, I think the education in identifying the side effect is the key because the drug is very effective.

So I do feel that it would be a positive impact in the community with a different toxicity profile, a little bit lower toxicity profile, especially in the indication like, say, mantle cell lymphoma. Of course the BTK inhibitors are the backbone, but having almost similar activity with a different agent with a different toxicity profile definitely has a role in the treatment paradigm of that particular cancer. So is the marginal zone lymphoma too.

Flinn: All right. Thank you.

Watch episode 1: Will Bispecific Antibodies Challenge CAR T-Cell Therapy in Follicular Lymphoma?

Watch episode 2: Lemzoparlimab Promising in Tough-to-Treat Lymphoma

Watch episode 3: Tisagenlecleucel Promising in R/R Follicular Lymphoma

Comment