ZUMA-3: CAR T Therapy for Adult Patients With ALL - Episode 4

The ZUMA-3 Trial: Efficacy and Safety Results


Primary investigator Bijal Shah, MD, MS, shares insights into the efficacy results of the ZUMA-3 trial of chimeric antigen receptor (CAR) T-cell therapy for acute lymphocytic leukemia (ALL), and Eunice Wang, MD, reviews the trial’s key safety data.

Bijal Shah, MD, MS: Regarding the key efficacy end points, we achieved our primary end point, which was overall response rate. This is a composite of complete remission [CR] and CR with incomplete platelet recovery [CRi]. This specifically was around 70%. The true CR rate was a little over 56%. The CRs were MRD [minimal residual disease]-negative. We weren’t able to get the MRD data from 1 patient, so we reported an MRD negativity rate of 97%. Importantly, the CRs were durable. When we look at duration of remission, this was quite prolonged—around 12 months overall—for all the patients, independent of whether they achieved a CR or CRi.

Importantly, these response data translated into a meaningful duration of remission, relapse-free survival [RFS], and overall survival. Specifically, in patients who achieved a CR or CRi, the median duration of response was a little over 12 months. For those who achieved a true CR—the majority of patients who achieved a response—we saw a median duration of response of almost 15 months. When we look at subsequent therapies, specifically allogeneic transplant, and censor for patients who underwent this procedure following CAR [chimeric antigen receptor] T-cell immunotherapy, we couldn’t show any benefit. In fact, at the data cutoff, 12 of the patients who achieved a CR/CRi were still in ongoing remission without having had a transplant. That speaks to the potential of this therapy as a definitive therapy. We won’t know until we have more data, more patients, and potentially even a randomization, rather than a simple statistical censoring, to help us understand the impact and the magnitude of benefit of transplant after CAR T-cell immunotherapy, but these are very promising.

When we think about the median RFS, there’s one thing I want to stress. We call it relapse-free survival according to this study design, but in terms of terminology, it equates to EFS [event-free survival] if you were to see it in a different study. We did not only study the RFS in responding patients. We studied it in all treated patients. Whether you want to call it RFS or EFS is fine. The median RFS was around 12 months. It was around 14 months in patients who achieved a CR or CRi.

Median overall survival was outstanding. The median was 18.2 months for the group. In those who achieved a CR or CRi, we haven’t yet reached median survival estimate. For the types of patients we enrolled, recognizing many had seen prior inotuzumab or prior blinatumomab, transplant and the like, these data are quite remarkable. I’m hopeful that this is going to be sufficient to merit FDA consideration and approval so we can begin utilizing this for our patients.

Eunice Wang, MD: The efficacy shown with this regimen was extremely high, with 71% of the 55 patients experiencing a CR or CRi following a single infusion of Kite CAR T cells. Currently, 31% of these patients remain in remission and are getting ongoing therapy. The median duration of the remission was also remarkable, with patients having responses lasting 12 months. Median relapse-free survival was over 12 months. Median overall survival for the patients was an impressive 18.2 months. To place this in context, our other treatments for relapsed/refractory B-ALL [B-cell acute lymphocytic leukemia], such as inotuzumab or blinatumomab given as single-agent therapies, have been associated with a mean duration of response or median overall survival ranging from 5 to 7 months. In my opinion, an overall survival of 18.2 months with this cohort after a single infusion was impressive. Median duration of the follow-up for these patients was also very reasonable: over 16 months of follow-up.

Adverse events were described for this patient population and may be of particular interest to community physicians and other providers. Half of patients developed anemia or neutropenia. About a quarter of patients developed immunological toxicity; specifically cytokine release syndrome [CRS], a neurological toxicity related to therapy. Immunological CRS and neurotoxicity greater than or equal to grade 3 and above generally occurred on days 5 to 9 of therapy and lasted a median of 7 days. These toxicities were largely reversible with administration of steroids and early administration of inotuzumab. However, there were 2 grade 5 events: 1 patient with a fatal brain herniation and a second patient with a septic syndrome. Overall, 10 out of the 55 patients proceeded on to subsequent allogeneic stem cell transplantation. The data, when censored for allogeneic transplantation, was not altered, with the median overall survival and duration of response remaining 18 months and 12 months, respectively.

When we talk about the potential practical implications of this therapy, a single infusion of this CAR T cell was associated with a significant grade 3 and above cytokine release and neurological toxicity in 25% of patients. The high efficacy rate of 71%, as well as the particularly long durability of these responses—lasting 18 months and, in some cases, has not yet been reached in the responding patients—is very impressive. As mentioned previously, we would anticipate that salvage chemotherapy, particularly for patients who had failed 2 to 3 lines of therapy, would be highly ineffective with only 10% to 20%, or 30% at best, of patients having a response to salvage chemotherapy following upfront chemotherapy.

Blinatumomab has been shown to have high response rates, particularly in patients with low-level disease, but the duration of these responses is only a matter of months. Similarly, with inotuzumab, we see limited durability with high response rates up to 80% in patients with first relapse B-ALL, but durability of response lasting only a matter of 6 months. Therefore, these data are highly encouraging and promising and are likely to set a new landmark in our treatment of relapsed and refractory disease in adult patients for whom CAR T-cell therapy, up until now, has been limited to only individuals younger than 25 years of age.

Transcript Edited for Clarity