番茄社区

Investigational bispecific antibody mosunetuzumab achieved deep and durable remissions as monotherapy for patients with heavily pretreated, relapsed or refractory follicular lymphoma, according to a presented at the recent American Society of Hematology (ASH) virtual meeting.

番茄社区 brought together three expert leaders in the field -- moderator , is joined by and -- for a virtual roundtable discussion. This first of four exclusive episodes focuses on the trial results and what the data might mean for the future of follicular lymphoma treatment.

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 gonna 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.

So Loretta, we've seen a number of new studies on follicular lymphoma also at ASH 2021 this year. One of them was the mosunetuzumab phase I/II trial in patients with follicular lymphoma. I think one of the thoughts is that perhaps these bispecific antibodies may displace CAR-T cells or at least give CAR-T cells a run for their money across a broad array of lymphomas. Here we have I think fairly impressive data with mosunetuzumab in follicular lymphoma. Can you walk us through that trial and the data?

Nastoupil: Sure. So mosunetuzumab is a CD20xCD3 bispecific antibody (Ab). And one of its advantages is that has a longer half-life than say blinatumomab. And so it allows for less frequent dosing. It also has a sub-Q formulation that's under development.

What was presented at ASH this year was the expansion study in relapsed/refractory follicular lymphoma. These were all patients in third line or later. They had all had a prior alkylator and CD20 antibody. They do receive a step-up dosing, because CRS [cytokine release syndrome] is a common side effect we see across all these bispecifics. And maybe the rates of grade two or higher might distinguish one from another.

But they get a step up, meaning a low dose on day 1, a little bit higher dose on day 8, and then finally full dose by day 15. And then they're dosed every 3 weeks beyond to either up to 17 cycles so there's a fixed of treatment with this agent as well, or if they're in a CR [complete response], they can stop after eight cycles.

And so again, in a pretty heavily pretreated patient population where other therapies that have been approved in the setting resulted a media PFS [progression free survival] of around 12 months, we see a median PFS of about 17 months in this patient population and in a good portion of patients that only had eight cycles of treatment, suggesting that the durability also is encouraging.

So I do think that this will challenge CAR-T in follicular lymphoma. And I think this offers an effective strategy for patients. I think the next wave is now to move it into earlier lines and in combination.

Flinn: Perfect. So Amit, what about this for the average community physician giving therapies for patients with follicular lymphoma? I mean, they have the PI3 kinase inhibitors, they have a variety of different options for patients. If ultimately this gets approved, where do you see it fitting into that monotherapy? And I guess also just the administration of it, if it's intravenous and the toxicity profiles.

Mehta: So bispecific antibodies, they are making their headwind actually, as Loretta mentioned. Impressive activity in POD24 and highly refractory, double refractory follicular lymphoma. And if you look at third line plus therapy for follicular lymphoma, maybe you're comparing with PI3 kinase inhibitor. They're oral, they have [an] added advantage being an oral health therapy compared to the bispecific antibodies. But the response rate and tolerability of bispecific antibodies, they're way better than the PI3 kinase inhibitors. Also, there are multiple combinations being explored, including with lenalidomide as well as polatuzumab, and all data were presented at ASH with very impressive activity. Including not only just mosunetuzumab, but glofitamab. Also both of them, they're being explored as a subcutaneous injection. Like we know epcoritamab as a subcutaneous injection.

So I think CAR-T has done one important thing, is to recognize and treat CRS and ICANS [immune effector cell-associated neurotoxicity syndrome]. So academic centers, they're very equipped to kind of identify those specialized side effects and treat them. I think, community, it will take a little while to kind of adapt to that. And importantly, we all know that these patients are being admitted in the hospital for a brief period of time to kind of observe, and if they develop CRS, they need tocilizumab or steroids. I'm not sure whether the community doctors would be able to have that facility with an expert team available on their hands to kind of deal with those.

PI3 kinase, as you know, that there are four different kind of PI3 kinase already approved in the follicular lymphoma setting. But they still are very active and they have a peculiar side effect in that setting. Compared to bispecific, the response rates are relatively lower. And uptake in the community is also lower because right from the beginning, diarrhea, transaminitis are challenging side effects including infections in this particular group of agents.

Flinn: So Loretta, do you think that this requirement for hospitalization or the need for having tocilizumab, or all these issues with cytokine release are permanent? Do you think that, when we know that some trials with some of the bispecifics don't necessarily require someone to be hospitalized? I mean, that could be a huge speed bump for community physicians and using this type of therapy.

Nastoupil: Yeah, I think it depends a little bit on which agents. So for instance, mosunetuzumab is no longer required for them to be preemptively hospitalized. The rates of grade two or higher CRS are exceedingly low. So that's a little bit different than, say, glofitamab, which we saw some data. But I think what all of the companies are doing and probably why it's delayed the approval in some sense, is trying to figure out mitigating strategies, because that will be a deal breaker.

To have to hospitalize someone just to observe them for potential toxicity is not really feasible. And then it's not really gonna replace CAR-T in my opinion. But if you could identify patients who are at risk and employ some of these strategies, so what they are looking at is more aggressive premeds -- so 20 milligrams of dexamethasone, for instance. The step up dosing, glofitamab is utilizing obinutuzumab, essentially compete with antigen binding sites, so you have less super-physiologic activation of T-cells during those first few weeks and then the sub-Q administration.

I think the other thing that we all need to do is as we gain more experience [is] be able to identify those patients who are at higher risk, which I'm sure it's going to be somewhat dependent on tumor burden and whether or not they have circulating malignant B cells. If we can do that and identify those that are never going to need hospitalization, then yes. I think it can be done safely.

Flinn: Perfect. Thank you.

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

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