Brexucabtagene Autoleucel Has Durable Efficacy in B-ALL, Irrespective of Age and Tumor Burden

Brexucabtagene autoleucel (Tecartus; formerly KTE-X19) demonstrated durable responses in heavily pretreated patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), according to long-term follow-up data from the phase 1/2 ZUMA-3 trial (NCT02614066).¹

Now, next steps are focused on better understanding the factors that contributed to durable remissions in select patients, determining the role of allogeneic stem cell transplant (ASCT) following this modality, and identifying ways to better leverage this product to further improve outcomes, according to Bijal Shah, MD, MS.

In October 2021, the FDA approved brexucabtagene autoleucel for use in adult patients with relapsed or refractory B-ALL based on earlier data from ZUMA-3.² Updated data presented during the 2022 ASCO Annual Meeting showed that the CAR T-cell therapy elicited responses in patients irrespective of age or baseline bone marrow blast percentage, although those with at least 75% bone marrow blasts at baseline derived less benefit.

Pooled data from both phases of the trial showed that among patients who achieved a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi; n = 57), the median overall survival (OS) with the therapy was 47 months (95% CI, 32.2­­–not estimable [NE]). Among all patients, the median OS was 25.4 months (95% CI, 16.2-NE).

Moreover, in patients with bone marrow blasts of no higher than 5%, those with bone marrow blasts higher than 5% but no higher than 25%, and in those with bone marrow blasts higher than 25% but not higher than 50%, the median OS with the CAR T-cell therapy was not reached (NR; 95% CI, 8.8 months-NE), 25.4 months (95% CI, 8.3-NE), and NR (95% CI, 9.0 months-NE), respectively.

“We need to find a way to get CAR T­-cell therapy into patients who have lower disease burdens. That is going to mean following patients for MRD recurrence and intervening quickly when we see those events emerge,” Shah said. “This may mean pushing CAR T into earlier lines of therapy. We must find a way to move beyond using CAR T-cell therapy as an agent of last resort. As we do that, [I believe] the outcomes will show us what we have already seen: that we can get durable remissions, improve survival, and change the trajectory of B-ALL.”

In an interview with OncLive^®, Shah, an associate member in the Department of Malignant Hematology at Moffitt Cancer Center, further discussed the long-term data from the ZUMA-3 trial of brexucabtagene autoleucel in patients with relapsed/refractory B-ALL and spotlighted additional areas ripe for further exploration.

OncLive^®: What are some of the questions you sought to answer with longer follow-up from the ZUMA-3 trial?

ZUMA-3 was a trial [that examined the] CAR T-cell therapy [brexucabtagene autoleucel] in adult patients with B-ALL. We wanted to show how these patients were doing [long term with the treatment]. That was a big question that evolved from the earlier presentation and publication of the phase 2 data.

Namely, [we wanted to know,] would the responses [achieved with the therapy] prove durable? Is there a concern using a CD28-based CAR T-cell therapy for ALL in terms of driving these more persistent, durable remissions? Is the therapy going to be associated with an impairment [or improvement] in survival? Are there features that are associated with poor responses [to this approach]? Are there things that we can do after the CAR?

[We had] a multitude of questions, and we wanted to try to do a deep dive and try to answer as much as we could.

What were the key findings presented during the 2022 ASCO Annual Meeting?

Patients appeared to show prolonged duration of remission, at [20.8] months in those patients with a CR [or CRi]. The patients are showing preserved OS, and the median OS was 47 months [in patients who achieved a CR or CRi] when we looked at our phase 1 and phase 2 populations combined. It is still a little hard for me to believe that the median OS was 47 months in a relapsed/refractory adult B-ALL population. How did we land here?

We want to try to understand the role of ASCT following CAR T-cell therapy. For patients who received the CAR and went on to ASCT while in a CR or CRi, we wanted to understand how they are now. [What we found] is fascinating: 6 out of the 10 transplanted patients are still alive and in ongoing remission. That is not what we would expect for a heavily pretreated population of B-ALL. We do not know if there is graft-vs-leukemia in B-ALL, but if it is there, it is modest.

What questions remain regarding ASCT?

We believe that a lot of the benefit that comes with an ASCT comes from conditioning. When you give total body irradiation or other chemical-based methods, the thought is that you are eradicating not just healthy marrow to make room for the transplanted cells, but you are also eradicating some amount of leukemia. It could be that the conditioning is providing some benefit; however, we do not expect [to see] that in heavily pretreated leukemia. We expect the opposite: that it would do nothing.

It makes me wonder if we over transplant some patients, [but we may never know for sure]. We will need to treat more patients and learn from real-world datasets whether there is any advantage. [In previous clinical trials of CAR T-cell therapy, researchers] could not see the benefit of an ASCT. In the pediatric real-world consortium datasets, they could not see the benefit of ASCT.

However, we must ask and answer the question specifically with brexucabtagene autoleucel [specifically]. I would guess that across the United States, we have real numbers. It has been [more than] 8 months since the FDA approval [of brexucabtagene autoleucel for treatment of adult patients with relapsed/refractory B-ALL], and that we will have some momentum to get a real-world registry moving forward, just like we have done in mantle cell lymphoma and diffuse large B-cell lymphoma.

What outcomes were observed in patients who did not undergo ASCT?

Six patients went on to receive subsequent anticancer therapy. One of the hard parts here is trying to understand the ‘why.’ These are patients who had not relapsed, so [that makes us question,] what was the feature that moved the physician to give a subsequent agent? We need to learn a little bit more. Maybe the patients had MRD, but it just was not detectable by flow cytometry, or maybe there was something else that we were not seeing that the investigators used to drive the decision to give additional anticancer therapy.

However, of those 6 patients, 4 are alive and still in remission. These are small numbers—I must emphasize that—but this is not what you would expect for relapsed/refractory B-ALL. Going back to the 55 patients [enrolled in the trial overall, 45%] received prior blinatumomab [Blincyto], 42% received prior ASCT, and 22% had prior inotuzumab ozogamicin [Besponsa]. So what was being used in these 6 patients? I would love to know. It would be great to try to learn from that experience, and hopefully those are data we will be able to generate as we go forward.

What about those who got nothing? They got CAR and then we stepped back and waited to see what happened next. Six patients are alive and in ongoing remission [out] of 23 evaluable patients. Certainly, I would want it to be all 23 patients [in ongoing remission], but it tells me that there is a significant cure fraction. I would be willing to bet, based on the DOR curves and OS curves that we generated as part of this abstract, that those 6 who are still in continuous remission are all patients who achieved true CRs after the CAR. I would be willing to bet that they came in with lower tumor burden. That may start to give us some insight into which patients we will need to more aggressively [consider] ASCT consolidation and which patients we can afford to watch.

We will know more about the ones we can afford to watch by looking at those 6 who [received] subsequent anticancer therapy. If we can achieve remissions in those patients with subsequent agents, who are those patients? If they are showing that these patients can achieve CR with CAR, maybe they can achieve CRs with other things? This is where I am intrigued to see what we can learn from each of these subgroups. We will continue to learn more as we go.

How did age influence response and toxicity with the agent?

I want to start with age because the data surprised me. Keep in mind, these are subgroup analyses with small numbers of patients, but we saw our best outcomes in [those between the ages of 18 years and 25 years] and those aged 65 years and above.

We had a 100% CR/CRi rate in the 65 years and older group, so they responded well to the therapy; however, I would not have anticipated that. I would have expected results to be [consistent with historic B-ALL survival rates]. The youngest [benefit the most], then, [with each] decade, [outcomes] get worse. However, that is not what we saw in the context of the CAR on this trial.

There may be other [factors]. Keep in mind that those patients who were in their 40s may have been more heavily pretreated, or there may be other things that are harder to look at in a univariate approach like we took here. However, increasing age did not necessarily come with worse outcomes. It was the youngest and the oldest who did best [with this therapy].

In terms of safety, [age] did not seem to matter; the younger patients and the older patients did equally well. When we looked at these different cohorts [by age], we could not see a signature for increased toxicity, and that was looking at grade 3 or higher neurotoxicity or grade 3 or higher cytokine release syndrome [CRS] by virtue of age; that surprised me. I would have expected those aged 65 years and older to do worse, but that is just not what we saw.

How did tumor burden influence outcomes?

[We know,] based on previous data with tisagenlecleucel [Kymriah], that patients with 5% and higher blasts experienced more toxicity [with the CAR]. The assumption was that increasing tumor burden would likewise be associated with a higher rate of CRS and a higher rate of neurotoxicity. Again, that is not what we saw. In fact, in those with the highest tumor burden, those who had 75% or higher blasts, we saw a trend toward lower high-grade CRS and lower high-grade neurotoxicity [rates].

We know from the ZUMA-3 analyses that the duration of remission, response, and T-cell expansion were all worse in the group with the highest blast burdens. We also know from the manuscript that those who had the most robust T-cell expansion were those who were most prone to develop high-grade toxicity. What we have identified here, is that in those patients who go into CAR with 75% and above blasts, we are not just getting the CAR expansion that we need. As such, we were not seeing the toxicity that would be commensurate with robust CAR T-cell expansion.

Because it was a response-driven trial, patients had to come on with 5% or greater blasts, making it difficult to answer certain questions. If we drew that line in the sand and if we treated [blast percentage] as a variable, we were not going to have the numbers to answer that. We did have 5 patients who were able to [improve] to less than 5% blasts. What we saw was 1 patient experienced grade 3 or higher CRS, and 1 had grade 3 or higher neurotoxicity.

What are the clinical implications of these data?

[The question is,] how do we move forward here? Treating low burdens of disease makes good sense. We were restricted in terms of our bridging strategies on the trial, but we can now use agents such as inotuzumab ozogamicin to try to deepen response, hopefully in a safer manner, to allow those patients to go on to CAR T-cell therapy.

We did have high-intensity chemotherapy regimens that were part of the trial. However, the challenge was that those patients were more prone to get sick and never make it to the CAR. As such, when we did the study, we were forced to use a low-intensity chemotherapy approach to keep the blast burden more or less stable.

However, this is the real world. We are not restricted to a 5% blast threshold, nor should we be. There are ample data—not just in the 5 patients we treated here, but in the pediatric real-world setting, showing that patients with low disease burden not only derive benefit, but derive the greatest benefit from CAR T-cell therapy.

References

1. Shah BD, Ghobadi A, Oluwole OO, et al. Two-year follow-up of KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult patients (pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) in ZUMA-3. J Clin Oncol. 2022;40(suppl 16):7010. doi:10.1200/JCO.2022.40.16_suppl.7010
2. US FDA approves Kite’s Tecartus as the first and only CAR T for adults with relapsed or refractory B-cell acute lymphoblastic leukemia. News release. Kite. October 1, 2021. Accessed June 28, 2022. https://bwnews.pr/3iq0Chg