Durable remissions were elicited with KTE-X19 in a majority of patients with relapsed or refractory mantle cell lymphoma, according to the updated results from the ZUMA-2 trial published in the New England Journal of Medicine. The treatment did, however, cause serious adverse events that were consistent with known toxicities of chimeric antigen receptor T-cell therapy.
Michael Wang, MD
Durable remissions were elicited with KTE-X19 in a majority of patients with relapsed or refractory mantle cell lymphoma (MCL), according to the updated results from the ZUMA-2 trial published in theNew England Journal of Medicine. The treatment did, however, cause serious adverse events that were consistent with known toxicities of chimeric antigen receptor (CAR) T-cell therapy.1
“ZUMA-2 is the first multi-center, phase II study of CAR T-cell therapy for relapsed/refractory mantle cell lymphoma, and these efficacy and safety results are encouraging,” said Michael Wang, MD, professor of lymphoma & myeloma, University of Texas MD Anderson Cancer Center, in a press release.2“Although this study continues, our reported results, including a manageable safety profile, point to this therapy as an effective and viable option for patients with relapsed or refractory mantle cell lymphoma.”
Seventy-four patients were enrolled in ZUMA-2 and went through leukapheresis. Overall, 68 patients received KTE-X19, out of 71 for whom the CAR T-cell agent was manufactured. From leukapheresis, the median time to receipt of KTE-X19 at the study location was 16 days. CAR T cell manufacturing failed for 3 patients, and all 3 did not proceed to additional apheresis. Of those for whom manufacturing was successful, 2 patients died from progressive disease (PD) before the receipt of conditioning chemotherapy. Following conditioning chemotherapy, 1 patient with active atrial fibrillation was considered ineligible for treatment with KTE-X19 because their condition was noted as part of the study exclusion criterion. For patients who were included in the final efficacy analysis, median follow-up was 12.3 months (range, 7.0-32.3).
All of the patients included in the efficacy analysis had disease that progressed on or after treatment with a Bruton’s tyrosine kinase (BTK) inhibitor and most patients had received at least 3 prior lines of therapy.
In the overall study population, 85% of patients had an objective response which included complete responses (CRs) in 59% of patients. This trend was consistent among the various subgroups. For the relapsed/refractory status subgroups, 92% of patients who relapsed after autologous stem cell transplant (SCT) had an objective response, as did 100% of patients who relapsed after their most recent previous therapy had an objective response, 92% of patients who were refractory to their most recent previous therapy, 92% of individuals who were refractory to BTK inhibition, 100% of participants who relapsed during or after BTK inhibition, and 67% of patients who could not receive BTK inhibition.
Across the subgroups of MCL, 91% of the 47 patients with classical MCL had an objective response. Of the 21 patients with pleomorphic MCL and blastoid MCL, objective responses were observed in 100% and 93%, respectively.
In all patients, the median time to an initial response was 1.0 month (range, 0.8-3.1), and the median time to a complete response was 3.0 months (range, 0.9-9.3).
There were 42 patients who achieved a partial response (PR) or stable disease (SD) initially, but then 57% of them subsequently achieved a CR in a median of 2.2 months (range, 1.8-8.3) after the initial response. At the time of data cut-off, responses were ongoing in 17 patients.
Twenty-nine patients were evaluated for minimal residual disease (MRD), and 24 were MRD-negative at 4 weeks; 19 of these patients had a CR and 5 had PRs. Additionally, 15 of the patients who were originally MRD-positive and had a response, were MRD-negative at 6 months. Second infusions of CAR T-cell therapy were given to 2 patients who had progression after achieving an objective response. These infusions began 1 to 1.3 years following initial treatment, and these patients continue to be evaluated for efficacy.
At data cutoff, 57% of all the patients in the primary efficacy analysis and 78% of the patients who achieved a CR were in remission. Forty-three percent of the first 28 patients who were treated continued their remission without additional treatment.
The estimated progression-free survival (PFS) rate at 1 year in patients included in the primary efficacy analysis was 61%. At 1 year, the estimated overall survival (OS) rate was 83%. In the subgroup analysis, PFS rates at 6 months were determined to be consistent across subgroups of patients with poor disease characteristics.
The safety analysis showed that every patient experienced at least one adverse event (AE). Ninety-nine percent of patients experienced a grade 3 or higher AE, with the most common being cytopenias (94%) and infections (32%). Additionally, cytokine release syndrome occurred in 91% of patients, with 15% being of grade 3 or high in severity, but no patients died from it.
Neurotologic events were observed in 63% of patients with a balanced proportion of grade 1/2 events (32%) and grade 3 or higher events (31%).
Serious AEs were seen in 68% of patients. Of the serious AEs observed, 32% of patients had grade 3 or higher infection, of which the most common was pneumonia.
Death occurred in 16 of the patients who received KTE-X19, which was mainly a result of disease progression (21%). Grade 5 AEs were observed in 2 patients. One of the grade 5 toxicities was related to conditioning chemotherapy and the other to CAR T-cell therapy.
The ZUMA-2 study was conducted at 20 sites throughout the United States and Europe. After condition chemotherapy with cyclophosphamide 500 mg/m2/day, administered on days −5 through −3, KTE-X19 2×106CAR T cells per kilogram of body weight was administered to patients on day 0.
The primary end point of the study was objective response rate, and the key secondary end points were duration of response, best objective response, PFS, and OS.
The efficacy analysis was powered to 96% to determine between an active therapy, with 50% of patients having an objective response, and a therapy that only 25% or less had a response, at a one-sided alpha level of 0.025. A total of 60 patients were analyzed for efficacy, per the study protocol. Investigators used the Wilcoxon rank-sum test for 2 independent samples and with the KruskalWallis test for the comparison of 2 or more independent samples to determine how KTE-X19 treatment correlated to CAR T-cell and cytokine levels in patients.
“This trial showed that a single infusion of KTE-X19 was capable of inducing durable remissions in patients with relapsed or refractory mantle cell lymphoma after the failure of BTK inhibitor therapy. The trial therapy led to serious and life-threatening toxic events that are largely consistent with those reported in previous studies of anti-CD19 CAR T-cell therapies in patients with aggressive B-cell lymphoma,” wrote Michael Wang, MD, et al.