Outcomes of Patients with Relapsed/Refractory Mantle Cell Lymphoma (R/R MCL) Treated with Brexucabtagene Autoleucel (Brexu-cel) in ZUMA-2 and ZUMA-18, an Expanded Access Study

Introduction: Brexu-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the United States for the treatment of adults with R/R MCL and in the European Union for adults with R/R MCL who received ≥2 prior therapies, including a Bruton tyrosine kinase inhibitor (BTKi). After a median of 35.6-months follow-up in the pivotal Phase 2, multicenter ZUMA-2 study, brexu-cel demonstrated an objective response rate (ORR) of 91%, a complete response (CR) rate of 68%, and a median overall survival (OS) of 46.6 months in all 68 treated patients with R/R MCL and a median OS not reached in patients with a CR (Wang et al. J Clin Oncol. 2022). ZUMA-18 is a multicenter, open-label, expanded access study of brexu-cel for the treatment of patients with R/R MCL. Here, we report OS outcomes after 4 years in ZUMA-2 and the primary analysis of ZUMA-18.

Methods: In ZUMA-2, adults (≥18 years) with R/R MCL with ≤5 prior regimens including a BTKi underwent leukapheresis and conditioning chemotherapy followed by one infusion of brexu-cel (2×10⁶ anti-CD19 CAR T cells/kg). ZUMA-18 consisted of 2 cohorts. The primary objectives were to provide access to brexu-cel for patients with R/R MCL until it was commercially available (Cohort 1) and patients with R/R MCL whose manufactured product did not meet commercial release specifications (Cohort 2). In Cohort 1, adults (≥18 years) with R/R MCL with ≥1 prior regimen underwent leukapheresis and conditioning chemotherapy followed by a single infusion of brexu-cel at a target dose of 2×10⁶ cells/kg (or fixed dose of 2x10⁸ anti-CD19 CAR T cells for patients who are ≥100 kg). In Cohort 2, patients received Cohort 1 treatment without leukapheresis (initial leukapheresis product used). Key endpoints were safety, ORR, and OS.

Results: As of July 23, 2022, median follow-up in all 68 treated patients in ZUMA-2 was 47.5 months (range, 37.9-68.3) and median OS was 46.4 months (range, 1.2-63.0) with 30 patients (44%) still alive. Median (range) OS for patients with CR (n=46), partial response (PR; n=16), and no response (n=6) were 58.7 (4.8-61.9), 16.3 (1.2-63.0), and 8.5 months (2.3-22.9), respectively.

As of February 3, 2023, 27 patients were enrolled in ZUMA-18 and 23 (Cohort 1, n=21; Cohort 2, n=2) received brexu-cel with a median follow-up of 33.5 months (range, 24.5-35.3). Median age was 69.0 years (range, 43-79); 78% were male; and median number of prior regimens was 4 (range, 1-10). The investigator-assessed ORR was 87% (95% CI, 66.4-97.2); 13 patients (57%), including both patients in Cohort 2, had a CR (95% CI, 34.5-76.8), 7 patients (30%) had a PR (95% CI, 13.2-52.9), and 2 patients (9%) had progressive disease (PD) as their best response to brexu-cel (95% CI, 1.1-28.0; 1 patient had not been assessed at data cutoff). The median OS was not reached (95% CI, 10.4-not estimable) at data cutoff with a 58% OS rate at 24 months (Figure 1). At data cutoff, 14 patients (61%) were still alive and 9 patients (39%) had died; 5 due to adverse events (AEs), 2 due to PD, and 2 due to other causes.

All 23 patients in ZUMA-18 experienced at least 1 Grade ≥3 AE and 18 patients (78%) experienced at least 1 Grade ≥3 treatment-related AE, of which, neutropenia (43%), anemia (30%), thrombocytopenia (30%), encephalopathy (22%), and leukopenia (22%) were most common. Grade ≥3 cytokine release syndrome and neurological events occurred in 1 patient (4%) and 8 patients (35%), respectively. Five Grade 5 AEs occurred, 1 that was deemed related to brexu-cel therapy (multiple organ dysfunction syndrome on Day 20) and 4 that were deemed unrelated to brexu-cel therapy (sepsis [2, Days 123 and 219], aspiration [1, on Day 49], and encephalopathy [1, on Day 68]).

The combined median OS for ZUMA-2 and ZUMA-18 patients (N=91) was 46.4 months (range, 0.7-63.0) with a 62% OS rate at 24 months (Figure 2).

Conclusions: With 4 years of median follow-up in ZUMA-2, patients continued to benefit from brexu-cel with a median OS of almost 5 years in patients with CR. Consistent with ZUMA-2 findings, brexu-cel demonstrated a high level of efficacy in patients with R/R MCL in ZUMA-18, with an ORR of 87% and median OS not yet reached at 33.5 months of follow-up. Additionally, no new safety signals were detected in ZUMA-18. Of note, given the small sample size (n=2), no definitive conclusions can be drawn from Cohort 2 outcomes alone. Together, these results support the continued use of brexu-cel in the R/R MCL setting.