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ASCO 2021 | ZUMA-3 study update: brexucabtagene autoleucel for R/R ALL
Bijal Shah, MD, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, discusses results from the Phase II ZUMA-3 study (NCT02614066), a multi-center international study investigating brexucabtagene autoleucel, formerly KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adults with relapsed/refractory acute lymphoblastic leukemia (R/R ALL). Patients were heavily pre-treated with immunotherapies such as inotuzumab and blinatumomab, and had high blast and tumor burdens. Results from the study reported an overall complete remission (CR) rate (CR + CR with incomplete hematologic recovery [CRi]) of 71%. Importantly, nearly all these remissions were measurable residual disease (MRD)-negative. The study also demonstrated improved median overall survival and duration of response. During the study, there were two mortalities that were attributable to the CAR T-cell therapy, one of which involved neurotoxicity. In particular, Dr Shah comments on the increased duration of remission and response in this population of heavily pre-treated R/R ALL patients and reports that next steps include integrating this immunotherapy earlier in the treatment regimen for ALL and elucidation of factors preventing progression to CAR-T therapy. This interview took place at the virtual European Hematology Association (EHA) Congress 2021.
Transcript (edited for clarity)
The ZUMA-3 trial presentation at EHA will be an encore presentation. The data will be presented at the American Society of Clinical Oncology meeting this Friday. We’ll be sharing the results of the Phase II study, or Phase II extension of ZUMA-3. This is a multi-center international study using a CAR T-cell immunotherapy with the CD28 co-stimulatory domain in adults with multiply relapsed and refractory acute lymphoblastic leukemia...
The ZUMA-3 trial presentation at EHA will be an encore presentation. The data will be presented at the American Society of Clinical Oncology meeting this Friday. We’ll be sharing the results of the Phase II study, or Phase II extension of ZUMA-3. This is a multi-center international study using a CAR T-cell immunotherapy with the CD28 co-stimulatory domain in adults with multiply relapsed and refractory acute lymphoblastic leukemia.
We treated adults up to the age of 84. The median age was around 40, and this was a heavily pretreated population so many of the patients had had prior inotuzumab, blinatumomab, allogeneic transplant and the like, and many came on with very high blast burdens. The median was around 65% or so. The patients received a single infusion of CAR T-cell therapy. This followed a standard lymphodepleting therapy with fludarabine and cyclophosphamide to help keep patients’ disease well-controlled while the manufacturing was being performed. We also allowed for bridging therapy. There were, I think it was one of six or so, defined bridging therapy options.
We enrolled 71 patients. We were able to treat 55 and we present the results in those 55 patients. We demonstrated a composite complete remission rate, so this is CR and CRI, of 71%. Of this, true CRs were around 56%. Nearly all of these remissions were MRD-negative, so ore specifically 97% were MRD-negative. There was one patient where we didn’t have a follow-up to assess MRD negativity. This translated into, you know, extended median overall survival, so it was 18.2 months overall. And in the group who achieved a CR, we haven’t yet reached the median overall survival. And, you know, this also translated into, you know, extended duration of response and the like.
I think the big key takeaway is we were able to do this safely. We did experience two related deaths on this trial. One was a case of cerebral edema with brain herniation, and one was an infection. These two mortality events though, were the only ones attributable to KTE, this therapy. And I think that that really stands out. We did see CRS and neurotoxicity grade three and four in around 25% of the patients for both of those toxicities respectively.
But, you know, apart from this one case of CNS herniation, all of the toxicity was reversible. So, for me the three main takeaways are we were able to treat patients safely and we were able to do so with a really high efficacy. Again, extended remission duration, extended overall survival. And so, when we think about this population, again, this heavily pretreated population with high tumor burden, I really think that these results are unparalleled. I think that this is better than anything we’ve seen to date in multiply relapsed ALL.
I think the next steps will be trying to understand how to integrate it earlier in the treatment paradigm. You know, you heard me allude to the fact that we treated 55 but enrolled 71. That means that there were several patients who didn’t make it to CAR T. And I think we can look at that and very easily see that, you know, infections and thrombosis, loss of eligibility, these were the key reasons why patients weren’t able to progress. And when we think about, you know, why is that the case? I mean, these are heavily pretreated leukemics, right? They have very little in the way of bone marrow reserve, very little in the way of functional reserve overall, you know, and so putting that in context, we understand, I think, that to really translate this into a successful therapy for all adult patients with relapsed ALL, we’re going to have to find ways to integrate this sooner.
So, we’re down in the multiply relapsed, post-transplant, post novel agent setting, but thinking about this really much earlier, you know, for relapse leukemics. And I think doing so will enable us to treat people before they’re critically ill and by virtue of doing so, be able to deliver the therapy in a situation where patients can actually receive it and can benefit from it.
I think that one of the caveats to this is this wasn’t really so much a function of manufacturing time. And that is something that I like to highlight. There’s always concerns when it takes three or four weeks to turn around CAR T-cells. And in this particular trial, we were able to manufacture CAR T-cells with a median of about two weeks. And this is really incredible, but that also speaks again to just how critically ill patients were when they were, when we were attempting to enroll them on the study.
I am really excited about these data. I think that it’s going to be a powerful adjunct for managing acute lymphoblastic leukemia. Again, we still have to go through, you know, the approval path and that’s still a process that’s ongoing. But provided this meets the threshold for regulatory approval, I’m really very eager to integrate it into the therapy for my patients, and I’m really hopeful that it will meaningfully change the benchmarks that we currently have.