Axicabtagene ciloleucel (axi-cel, Yescarta) demonstrated a significant and clinically significant improvement in event-free survival (EFS) compared to standard care as a second-line treatment for relapsed or refractory large B. cell lymphoma (LBCL), according to the ZUMA-7 assay. The results were presented at this month’s American Society of Hematology (ASH) Virtual Meeting.
MedPage today brought together three expert leaders in the field: moderator Ian Flinn, MD, is joined by Loretta Nastoupil, MD, and Amitkumar Mehta, MD, for a virtual panel discussion. This second of four exclusive episodes focuses on the results of phase III ZUMA-7 trial.
Here is a transcript of what they said:
Flinn: Hi, I’m Ian Flinn from the Sarah Cannon Research Institute in Nashville, Tennessee. With me today are Loretta Nastoupil from the MD Anderson Cancer Center and Amit Mehta from the University of Alabama in Birmingham. We’re going to talk about some of the exciting news coming out of ASH 2021.
Well, maybe we can change now and talk a little bit about the CAR-T cell trials. There have been some really exciting CAR-T cell trials presented to ASH this year trying to move therapy to the third line, primarily patients who have relapsed after autologous transplant or had refractory disease and were eligible for transplant. , in the second line and replacing the graft. So Amit, there was this big international trial, the ZUMA-7 trial that compared axi-cel to standard therapy with lifesaving therapy and autologous transplant. Can you tell us a little more about this essay and what you think of the results – this is a plenary study, so a very important essay.
Mehta: Yes you are right. Fred Locke presented in plenary ZUMA-7, which was a randomized phase III trial comparing axi-cel to standard therapy in patients with relapsed / refractory large B-cell lymphoma. Thus, in this study, patients were randomized between two arms. One arm was the axi-cel arm where they had lymphodepletion followed by CAR-T, while the other arm was the standard treatment for which they received intensive chemotherapy followed by a transplant. And these two were compared to a primary endpoint of event-free survival.
This was the first study to look at face-to-face transplantation in the first relapse of large B cell lymphoma. Most patients have primary refractories, so they relapsed within a year. their initial treatment. And the study randomized 359 patients into these two arms. And the study met the primary endpoint of event-free survival between these two arms. Thus, event-free survival for the axi-cel arm was 8.3 months, and for the standard of care arm was 2 months.
Some of the highlights of the study it is important to note that the bridging treatment for patients randomized to the axi-cel arm was not allowed, only steroids were allowed. There were therefore comments as to whether the patients in this arm who were selected were not aggressive. So that’s something to keep in mind. The other important side effect profile of axi-cel was also consistent as published before CRS [cytokine release syndrome] and ICANS [immune effector cell-associated neurotoxicity syndrome] occurred in a CAR-T or axi-cel arm as previously published. Six percent of patients had grade three or greater CRS and 21% had grade three or greater ICANS.
So, in my opinion, this will definitely be a practice that will change for primary refractory patients. As I mentioned, there has been some debate as to whether we want to select patients who are definitely refractory or who relapse within a year, and those who can be treated only with high dose steroids instead. than to supplement aggressive chemotherapy. Thus, patient selection will be key, but this could be used more in the setting of first relapse refractory patients for axi-cel.
Flinn: Loretta, are you okay, is that what we’re gonna do? And I guess it might be enough to reduce the profile of adverse events a bit. They are different between a stem cell transplant and immunotherapy, in particular axi-cel. What do you think about that?
Nastoupil: I think the key aspect of this study is that this is really the best approach for second-line large cell lymphoma in a high risk patient population. In fact, there was not a large portion of the patients in the control arm who were successful in obtaining a high dose autograft, reflecting the fact that, again, these were patients with high dose. high risk who progressed early from first-line rituximab. [Rituxan] and chemotherapy. So no wonder a lot of it never gets there. So it’s really a CAR-T versus salvage chemotherapy, and then some of it actually gets transplanted. So I agree. It is the practice that is changing.
Now the challenge is, do we extrapolate? Are we now taking patients who progress in 15 months or 18 months in CAR-T and in second line? I think we should probably always reserve it for those high risk patients, as these are the ones we thought didn’t do as well with the lifesaving chemo and high dose therapy. And axi-cel’s safety profile, treatment-related mortality was pretty low, but again, it’s not really head-to-head versus auto.
Flinn: Because of the lifesaving chemotherapy in there. And you are not …
Nastoupil: Yeah. And the fact that a minority actually goes to autograft.
Flinn: Yeah. I guess the other thing that was at least important was that you think, well, okay, you can just go ahead and get a rescue with CAR-T cells if you don’t respond. lifesaving chemotherapy and transplant. But clearly, the order made a difference here, didn’t it? I mean, there is a huge difference and not everyone could access CAR-T cells if they didn’t respond to lifesaving therapy. Yes, I think that’s another important part of that too.
Amit, if you look at the curves presented by Dr. Locke, the control arm performed pretty much as you would expect. I mean, less than 20% of those patients had significant progression-free survival, whereas the investigative arm, the CAR-T cell arm, had about double that. I mean, it was an awesome difference. It’s not just a statistically significant difference. This is a clinically significant difference in my opinion. What is your opinion on this?
Mehta: No it’s true. As I mentioned, there has certainly been a significant improvement, but at the same time, patient selection is key. And as Loretta mentioned, it was a surprise to me that of the patients randomized to the control arm, about a third could make it to the transplant. So selecting the patients in my opinion will be the key to seeing the best benefit. And that will be an extrapolation. There is no doubt in a real environment. And I also feel like in the real world the control arms usually in a clinical trial work better than in the real world. But the question remains as to why only a third of patients could make it to the transplant.