Bijal Shah, MD, MS, discusses the key findings of the ZUMA-3 trial, as well as key safety information regarding brexucabtagene autoleucel as a treatment for patients with heavily pretreated patients with relapsed/refractory B-cell ALL.
Brexucabtagene autoleucel (formerly KTE-X19; Tecartus) has shown promising clinical benefit with low rates of cytokine release syndrome (CRS) and neurotoxicity in heavily pretreated patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-cell ALL), according to Bijal Shah, MD, MS.
On April 2, 2021, a supplemental biologics license application was submitted to the FDA for brexucabtagene autoleucel for the treatment of adult patients with relapsed/refractory B-cell ALL based on the results of the phase 1/2 ZUMA-3 trial (NCT02614066).1 The phase 2 results of the study, which were presented at the virtual2021 European Hematology Association Congress, indicated that after a median follow up of 16.4 months, patients experienced a complete response (CR) and CR with incomplete blood count recovery (CRi) rate of 71%, with 31% of responders experiencing ongoing responses.2
“I am excited and hopeful that we can begin to move this [treatment approach] forward into earlier lines of therapy, thinking not just about broadly relapsed ALL, but [also] frontline disease, [as well as] simplifying therapy, shortening therapy and hopefully coming up [with better outcomes] than we were with our standard chemotherapeutic,” Shah said.
In an interview with OncLive®, Shah, an associate member in the Department of Malignant Hematology at Moffitt Cancer Center, discussed the key findings of the ZUMA-3 trial, as well as key safety information regarding brexucabtagene autoleucel as a treatment for patients with heavily pretreated patients with relapsed/refractory B-cell ALL.
When we talk about adults with ALL, we are struck by 2 major problems. One [is that] the majority [of patients] relapse. When we look at survival rates in adults, even using the most recent SEER data, we are talking about a 38% survival rate at 5 years and, again, most of that is governed by relapse. When we project forward to what happens when adults relapse, the outcomes are quite poor. We know that with blinatumomab [Blincyto], if we can integrate it for minimal residual disease [MRD] relapses or those who have persistent MRD on therapy, using [it] and subsequent transplant can save approximately 50% of patients. If we, however, try to come in later, when patients have morphologic relapse—more than 5% blast in their bone marrow—whether we are talking about blinatumomab or inotuzumab ozogamicin [Besponsa] as a bridge to subsequent transplant, we are still batting somewhere between 10% and 20% [in terms of] long-term survival. That is not good. If we go a step beyond that and ask, ‘What is the percentage of patients who are even making it to these therapies or to transplant?’ The numbers get progressively smaller.
That is the background that we are talking about when we ask what we can do to improve outcomes for patients with relapsed ALL. Speaking specifically about brexucabtagene autoleucel, this particular trial targeted individuals who were either primary refractory or those who were in second or greater relapse. That means they were in the third-line setting and beyond. The therapy was most often integrated after transplant, after blinatumomab, or after inotuzumab ozogamicin. If you look down the line, the percentage of patients who had these therapies is quite high. Nearly half of the patients [on the study] have had one more of these therapies. It is telling about what we know in terms of relapsed B-cell ALL. It is still an unmet medical need, so hopefully CAR T-cell therapy will help to fill that space.
This trial was developed for adult patients [who were] 18 [years or older], with relapsed B-cell ALL [who received] at least 2 prior lines of therapy or were primary refractory. Patients could enroll if they had Philadelphia chromosome–positive disease. [Patients] had to show CD19 expression. One of the things we had to keep in mind was that patients could have been treated with prior blinatumomab [and], in fact, many were. We needed to make sure that CD19 was still expressed by the blasts. Now, that was not a centralized assessment or any kind of specialized research assessment—that was just dictated by the local institutions, [which] would [confirm if the patient] was CD19-positive. Based on that, it allowed for enrollment to the study
[Patients] did have to have higher than 5% blasts to enroll and we did not allow patients who had MRD to enroll on the study. In fact, when we look at patients who ultimately did not go on to receive the infusion—in total we enrolled 71 [patients] and treated 55—and when we talk about failing to meet eligibility, these were the issues that arose. In the case of 1 patient, they did not meet the 5% blasts threshold, and in the case of another, we could not show that they were still CD19-positive. This is what we mean by loss of eligibility. These are things that were important in terms of the study design.
The primary end point was overall response rate [ORR], [which was a] composite of complete remission/complete response with CR/CRi. The secondary end points included overall survival [OS], relapse-free survival [RFS], and duration of response [DOR].
The true CR rate was approximately 56%, and this is [very] telling. These CR rates translated into improved RFS, improved OS, and improved DOR well beyond our expectations. If we just focus on those who had a CR/CRI, the median OS still has not been met. When you think about the population that we are [treating], that is really quite remarkable.
There are 2 pieces that are important when we talk about safety. The first piece begins before we even administer the CAR T-cell therapy. I had mentioned that there were several patients who came off [the study] because of eligibility concerns, meaning they did not have CD19 expression or they did not meet the 5% blasts threshold. It is [also] important to keep in mind that there were several other patients who did not make it to infusion because of infection or blood clots. That is important when we talk about intent-to-treat analyses. We have to keep that in mind as we figure out how to apply this therapy in the real-world setting. Certainly, we are going to be much more willing to infuse the CAR T cells in patients who may not meet the strict eligibility, but I do not think any of us would go forward with chemotherapy conditioning [with] fludarabine and cyclophosphamide or the T-cell infusion itself in someone who has an advanced infection. That would not be in the patient's best interest.
That tells us a lot about what adult ALL is. Many patients do not make it to second- and third-line salvage [therapy] when we look at adult ALL, as a whole. Infections and decompensation in terms of their performance status, [as well as] other comorbidities start to become amplified in this setting because they have no meaningful physiologic reserve. We saw that on this trial.
When we talk about safety, the first thing we must keep in mind is that we need to figure out a way to integrate CAR T-cell therapy in the real-world setting earlier. If we try to come in after patients have had multiple lines of therapy, we can anticipate that they will have poor physiologic reserve, poor amount of hematopoietic reserve. They are going to have infections and clots, and we are never going to be able to make this real. The first critical element when it comes to safety is trying to figure out how we get it in earlier, [to ensure] that we are not finding ourselves battling more than 1 problem at a time.
The second thing, when it comes to safety, is what happened for those who were infused. The good news is most of the toxicity was consistent [with] what we saw in the phase 1 trial. We saw anemia, thrombocytopenia, and fevers. We did unexpectedly see 1 case of cerebral edema, which was fatal for 1 of our patients. It is still hard for me to wrap my head around it. On the one hand, we must acknowledge that this is a CAR T-cell–associated toxicity, but on the other hand, we must acknowledge that it is extraordinarily uncommon. If we look across all the trials that have been done to date, we are talking about a very small percentage. The other thing that is interesting about the about brain swelling is, although we classify it as a neurologic toxicity because it impacts the brain, why is it occurring during the CRS phase? That [is a] period where we see fever and hypotension. Why is it occurring during that initial phase as T cells are expanding and doing their job of killing leukemia? It is rare and it is occurring when it is not supposed to, meaning, it is earlier than most cases. To be blunt, we do not understand the biology of it, period. That is something that we all want to be able to understand and hopefully prevent as we move forward.
One of the things that I was really excited about on this trial was the early initiation of tocilizumab [Actemra] and steroids. We intervene for very low-grade toxicity to try and prevent these events. I would say that also underscores the success that we saw as it relates to safety. If you look overall, we had an approximately 25% grade 3 and above CRS rate, and approximately a 25% grade 3 and above neurotoxicity rate. For an adult population with high burden ALL, that is also unparalleled. Those rates are not that dissimilar from what we saw in large cell lymphoma and mantle cell lymphoma. I am quite proud of achieving those benchmarks. Again, it is because of the early intervention that we were able to mitigate much of the toxicity.
Interestingly, the early initiation of tocilizumab and steroids did not seem to come with any impact on response. Often, steroids are fine, you just have to control them. Steroids for 2 weeks is probably not fine, but a short exposure to steroids if we believe the patient needs it is probably going to be okay, and we are not really going to impair the efficacy of the CAR T-cell therapy. The same thing goes for tocilizumab, where we cannot show that there is any impact. With very simple measures [done to control] the toxicity, we can really improve the course [of treatment] for a lot of our patients.
If you read between the lines, where we saw our best responses, but also where we saw toxicity, and if you understand that we were intervening early for that toxicity, you will see that despite early intervention in those who had grade 2 and above CRS, despite early intervention for neurotoxicity, we still see phenomenal expansion. That also translated into a higher likelihood of CR.