The objectives of the study were to determine the safety and efficacy of brexucabtagene autoleucel in patients 21 years of age or younger with relapsed/refractory B-cell ALL or non-Hodgkin’s lymphoma. The primary endpoint of Phase 1 was the incidence of dose-limiting toxicities (DLTs) with the key secondary endpoints of CR plus CR with percent incomplete haematological recovery (CR/CRi), relapse-free survival (RFS), pharmacokinetics/pharmacodynamics, duration of response (DOR), and overall survival (OS).
All patients were screened prior to leukapheresis and, at the discretion of the treating investigators, were allowed to receive bridging therapy, i.e. completed treatment 7 or more days prior to 5 pre-chemotherapy half-lives for the condition. Treatment consisted of a preliminary regimen of fludarabine at 25 mg/m2 on days -4 to -2 plus cyclophosphamide at 900 mg/m2 on days -2, followed by brexucabtagene autoleucel infusion at target doses of 1 × 106 or 2 × 106 CAR -positive T cells.
At the September 9, 2020 data limit, the median follow-up was 36.1 months with 24 patients receiving brexucabtagene autoleucel. The median time from leukapheresis to brexucabtagene autoleucel production was 14.0 days for all patients; leukapheresis to infusion time averaged 27.0 days.
Patients treated with the dose of 2 × 106 (n = 4) had a CR/CRi rate of 75%. In patients treated with the doses of 1 × 106, 68 ml (n = 11) and 1 × 106, 40 ml (n = 9) the rates of CR/CRi were 64% and 67%, respectively. The percentage of CR/CRi in the entire patient cohort was 67%. One patient in the 1 × 106.68 mL had a CR with partial hematologic recovery and 1 in the 1 × 106.40 mL group had hypoplastic/aplastic bone marrow. One patient in each of the 1 × 106 dose groups did not respond to treatment. Rates of MRD negativity in the 2×106; 1×106.68ml; and the dose groups of 1 x 106.40 ml were 75%, 73% and 78%, respectively.
Across doses, patients with prior treatment with blinatumomab (Blincyto; n = 8) experienced a CR/CRi rate of 38%. All patients previously treated with an allogeneic stem cell transplant (alloSCT; n = 6) had a CR/CRi rate of 86%. There was a CR in 1 patient who had previously received inotuzumab ozogamicin (Besponsa).
Patients who achieved CR/CRi (n=16) subsequently received alloSCT in 87.5% of cases, with a median time to transplant of 2.3 months (range 1.4-24.9).
The median DOR in the 2 × 106 dose group was 4.1 months (95%, not evaluable [NE]-NE). In the 1 × 106.68 mL and 1 × 106.40 mL dose groups, the DOR was 10.7 months (95% CI, 7.2-14.2) and not reached (95% CI, NE-NE). DOR in 16 patients with CR/CRi was 7.2 months (95% CI, 0.03-14.2).
Median RFS in the 1 × 106, 40 mL dose group was not achieved. In the dose groups 2 × 106 and 1 × 106, 68 mL, the median RFS was 5.2 months (95% CI, 0.03-5.2) and 9.1 months (95% CI, 0.03- 17.8).
The median OS in the 2 × 106 dose group was 8.0 months (95%, 0.5-NE) and was not achieved in any of the 1 × 106 dose groups. The percent OS at 24 months in the 1 × 106, 40 mL dose group was 87.5% (95% CI, 38.7-98.1).
The researchers reported that “58% of treated patients (n = 14/24) were still alive and in ongoing follow-up from the time the data was closed.”
The peak expansion of CAR T cells was similar between doses, but was greatest in the patients receiving brexucabtagene autoleucel at 2 × 106 CAR-positive T cells. Patients with CR/CRi and patients who achieve MRD negativity show the greatest expansion after infusion.
In terms of safety, no DLTs were observed in the 3 patients evaluable for DLT. Serious adverse events (AEs) occurred in 71% of patients and 8 patients (33%) died during the study. Deaths were attributed to disease progression in 6 participants and adverse events other than grade 5 B-cell ALL in 2. The 2 grade 5 events were disseminated mucormycotic and Escherichia sepsis.
Specifically, there were no reports of grade 4 or 5 cytokine release syndrome (CRS). In all patients, CRS occurred in 88% and Grade 3 CRS in 33%. Three of 4 patients treated with the 2 × 106 dose had Grade 3 CRS, with an incidence of less than 30% in the 1 × 106 dose groups. The median time to onset in the overall group was 5 days ( range, 1-14) and was 2 days (range, 1-4) in the 2 × 106 dose group. All events of CRS were resolved.
Neurologic events generally occurred in 67% of patients with only 1 grade 4 brain edema reported in the 1 × 106.68 mL group. Grade 3 neurologic events occurred in 17% of patients overall and in 25% of those in the 2 × 106 dose group. Two of the 16 neurologic events did not resolve at time of death, 1 each from progressive disease and one AE unrelated to brexucabtagene autoleucel.
Patients with B-cell ALL were eligible for brexucabtagene autoleucel therapy if they had 5% or more bone marrow blasts; had recurrent or refractory Philadelphia chromosome-negative disease; adequate organ function; and a Lansky or Karnofsky performance status of 80% or higher. Prior treatment with blinatumomab required patients to have leukaemic blasts with CD19 expression of 90% or greater.
The Phase 2 portion of the study is currently enrolling patients with relapsed/refractory B-cell ALL with expanded inclusion criteria. brexucabtagene autoleucel is currently approved for the treatment of adult patients with relapsed/refractory mantle cell lymphoma2 and numerous clinical studies are underway in other treatment settings.
Wayne AS, Huynh V, Hijiya N, et al. ZUMA-4 phase 1 long-term results: kte-x19 chimeric antigen receptor T-cell therapy in pediatric/adolescent patients with relapsed/refractory B-cell acute lymphoblastic leukemia. Presented at: 2021 European Society of Hematology Congress; June 9-17, 2021. Virtual. Accessed June 11, 2021. https://bit.ly/3gti2biFDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. FDA. July 24, 2020. Accessible on June 11, 2021. https://bit.ly/3gHlK1d