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After a long string of clinical trial success in hematologic malignancies, chimeric antigen receptor (CAR) T-cell therapy failed to improve event-free survival versus standard of care for primary refractory/relapsed aggressive B-cell non-Hodgkin lymphoma, according to findings presented at the 2021 American Society of Hematology (ASH) meeting.

MedPage Today brought together three expert leaders in the field: Moderator , is joined by , and , for a virtual roundtable discussion. This third of four exclusive episodes focuses on the results of the international .

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 of ASH 2021.

So our next topic, let's talk about CAR-T cells in the second-line management of patients with large cell lymphoma. We've seen several trials that were presented at ASH this year regarding that topic. One was the BELINDA trial. The BELINDA trial was a large international phase III trial comparing tisa-cel [tisagenlecleucel; Kymriah] to standard of care, either chemotherapy or chemotherapy ultimately going on to transplant, in the second-line setting. So Loretta, maybe you can walk us through that trial.

Nastoupil: Sure. So the BELINDA study looked at tisa-cel, which is a 4-1BB construct versus salvage chemotherapy and high-dose therapy in those similar high-risk patients, those that progress within 12 months of frontline rituximab [Rituxan] and anthracycline-containing therapy.

There was clearly a difference in this study in terms of the schema. And so what I mean by that is there was a much larger proportion of patients randomized to CAR-T that actually got bridging or salvage chemotherapy as opposed to the ZUMA-7 study. As a result, there was a week-6 response that was done in both arms that didn't count in terms of events, similar to ZUMA-7. Event-free survival was the primary endpoint. But the timeline in terms of when events counted towards that primary analysis was different. There was also a delay, in my opinion, from enrollment to undergoing cell infusion among the patients on the experimental arm of about 52 days versus 29 days that we saw in the ZUMA-7. And there was a skewing in the patient characteristics, meaning there were high-risk patients enrolled on the tisa-cel arm. So for instance, higher percentage of patients with high grade B-cell lymphoma or those with high IPI [international prognostic index].

That being said it was a negative study. Tisa-cel did not perform well. It was not better in terms of efficacy or safety. Similar outcomes in the control arm in comparison to ZUMA-7, suggesting that we can kind of now compare across these studies, given they were done in a similar patient population, the control arm performs similarly. And so it's hard not to conclude that tisa-cel is just a less effective CAR-T. But I think the other big takeaway is we need to get patients to treating centers as early as possible if CAR-T is something that we think is important in that treatment landscape.

Flinn: So just to follow-up on that, as you mentioned there was no difference, but the patients who were treated with tisa-cel, they had a worse outcome than if you were to use it in third line. And so I'm having a hard time wrapping my head around that one. I mean, all the things you said are absolutely true in terms of delay to therapy maybe a little bit high-risk patient population. But do you think that's the only explanation here? I mean, how do you reconcile that with the third-line data?

Nastoupil: I mean, it's contradictory to what we think in that moving it into earlier lines of treatment, where patients are less heavily pretreated, you'd have a younger fitter T-cell that's going to be performing better. I think the challenge is if we saw some that also looked at their real-world outcomes of tisa-cel versus axi-cel [axicabtagene ciloleucel; Yescarta], and though the overall survival was no different, the tisa-cel arm also had a median [progression-free survival] of about 3 months. Now, again that's in the third-line setting. So this at least tells me that there is something probably inherently different about these constructs. And that tisa-cel is probably not as effective as what we see with liso-cel [lisocabtagene maraleucel; Breyanzi] for instance. And it's probably going to be harder now to have a role in the management of large cell lymphoma.

But you're absolutely right. It did not perform any better and potentially worse than expected when it got moved into earlier lines, but maybe it's a higher-risk patient population too. The JULIET study took relapsed or refractory patients and there was probably at least half of the patients that were just relapsed. And so this is a sort of potentially higher-risk group where it's being tested as well.

Flinn: Amit, any other thoughts on the BELINDA trial? Anything else you'd like to add to that?

Mehta: I totally agree with Loretta, and I think the key is, when we want CAR-T to work, we want to make sure that these patients, they don't wait longer. You know, 56 days is too long. And I think that's why the over-the-shelf CAR-T is becoming popular because that timing is shorter and shorter. So, that's one, and second of course is the side effect profile. With tisa-cel all 4-1BB products have relatively safer side effect profiles. But the key is patient selection, and second is earlier preparation of CAR-T cell products.

Flinn: Great. Thank you.

Watch Episode 1: Is Second-Line Axi-Cel the New Standard in Aggressive B-Cell Lymphoma?

Watch Episode 2: Finally, a Positive Study in First-Line DLBCL Treatment. What Will it Mean?

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