乌鸦传媒

The chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (axi-cel, Yescarta) demonstrated significant and clinically meaningful improvement in event-free survival (EFS) compared with standard of care as second-line treatment for relapsed or refractory large B-cell lymphoma (LBCL), according to the . The findings were presented at this month's American Society of Hematology (ASH) virtual meeting.

乌鸦传媒 brought together three expert leaders in the field: Moderator , is joined by , and , for a virtual roundtable discussion. This second of four exclusive episodes focuses on the results of the phase III ZUMA-7 trial.

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 of ASH 2021.

Well, maybe we can switch now and talk a little bit about CAR-T cell trials. There were some really exciting CAR-T cell trials presented this year at ASH trying to move the therapy from third line, basically those patients who relapsed after an autologous transplant or had refractory disease and were eligible for a transplant, to second line and replacing transplant. So Amit, there was this large international trial, the ZUMA-7 trial that compared axi-cel to standard of care therapy with salvage therapy and autologous transplant. Can you tell us a little bit about that trial and what your take is on the results -- it's a plenary session study, so a very important trial.

Mehta: Yeah, you're right. Fred Locke presented in plenary session ZUMA-7, which was a phase III randomized trial of axi-cel versus standard of care therapy in patients with relapsed/refractory large B-cell lymphoma. So in this study, the patients were randomized between two arms. One arm was the axi-cel arm where they got lymphodepletion followed by CAR-T, while the other arm was standard of care that they got intensive chemotherapy followed by transplant. And these two were compared with a primary endpoint of event-free survival.

This was the first study looking at head-to-head with the transplant in first relapse of large B-cell lymphoma. Most of the patients have primary refractory, so they had relapse within a year of their initial treatment. And the study randomized 359 patients in these two arms. And the study met the primary endpoint of event free survival between those two arms. So the event free survival for axi-cel arm was 8.3 months, and for the standard of care arm was 2 months.

Some of the highlight of the study, which is important to note that bridging therapy for those patients were who were randomized to axi-cel arm was not allowed, only steroids were allowed. So there were some comments whether the patients on that arm that were selected were not aggressive. So that's something to keep in mind. The other important axi-cel side effect profile was also consistent as published before the CRS [cytokine release syndrome] and ICANS [immune effector cell-associated neurotoxicity syndrome] occurred in a CAR-T or axi-cel arm as published before. Six percent of patients had grade three or more CRS and 21% had grade three or more ICANS.

So in my opinion, definitely this will be a practice changing for primary refractory patients. As I mentioned that there were debates whether we want to select those patients who are definitely refractory or relapse within a year, and those who can be handled just with high dose steroid rather than bridging aggressive chemotherapy. So patient selection will be the key, but this might be used more in setting of first relapse refractory patients for axi-cel.

Flinn: Loretta, do you agree, is this what we're gonna be doing? And I guess maybe just dial down a little bit on the adverse event profile. They're different between a stem cell transplant and immunotherapy, especially axi-cel. What do you think about that?

Nastoupil: I think the key aspect of this study is this is really what is the best approach to second line large cell lymphoma in a high risk patient population. There's actually not a huge portion of patients in the control arm that actually made it to high dose therapy auto transplant, reflective of the fact that, again, these were high risk patients that have progressed early from frontline rituximab [Rituxan] and chemotherapy. So not surprising that a large portion never make it. So it's really CAR-T versus salvage chemotherapy, and then a portion of those actually go on to transplant. So I do agree. This is practice changing.

Now the challenge to that is, do we extrapolate? Do we now take patients that progress in 15 months or 18 months to CAR-T and second line? I think we should probably still reserve it for these high risk patients, because they're the ones that we anticipated were not gonna do as well with salvage chemo and high dose therapy. And the safety profile of axi-cel, the treatment related mortality was quite low, but again, it's not really head-to-head versus auto.

Flinn: Because of the salvage chemotherapy that was in there. And you're not...

Nastoupil: Yeah. And the fact that a minority actually go on to auto transplant.

Flinn: Yeah. I guess the other thing that was important at least is that you think, well, okay, you can just go ahead and get salvage with with CAR-T cell if you don't respond to the salvage chemotherapy and transplant. But clearly, order made a difference here, right? I mean, there is a huge difference and not everyone could get to CAR-T cells if they didn't respond to the salvage therapy. Yeah, I think that's another important part of this as well.

Amit, if you look at the curves that were presented by Dr. Locke, the control arm performed pretty much as you would expect. I mean, less than 20% of those patients had meaningful progression-free survival, whereas the investigation arm, the CAR-T cell arm, had roughly doubling of that. I mean, this was an impressive difference. It's not just a statistical significant difference. It's a clinically meaningful difference in my view. What's your take on that?

Mehta: No, that is true. As I mentioned, that there was definitely a meaningful improvement, but at the same time, the patient selection is the key. And as Loretta mentioned, it was a surprise to me that the patients randomized to the control arm, about one-third could make it to the transplant. So the patient selection in my opinion will be the key to see the best benefit. And that will be extrapolation. There is no doubt in a real world setting. And I also feel that in a real world setting, the control arms usually in a clinical trial setting perform better than a real world. But the question remains that why only one-third of patients could make it to transplant.

Watch Episode 1: Finally, a Positive Study in First-Line DLBCL Treatment. What Will it Mean?

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