Primary Analysis of ZUMA-2 Cohort 3: Brexucabtagene Autoleucel (Brexu-Cel) in Patients (Pts) with Relapsed/Refractory Mantle Cell Lymphoma (R/R MCL) Who Were Naive to Bruton Tyrosine Kinase Inhibitors (BTKi)

Introduction: Brexu-cel is an autologous anti-CD19 CAR T-cell therapy approved for adults with R/R MCL in the US and EU (after ≥2 prior lines of therapy [LoT], including a BTKi in EU), based on results from Cohort 1 of ZUMA-2 (NCT02601313). Brexu-cel demonstrated an objective response rate (ORR) of 91%, a complete response (CR) rate of 68%, and a median overall survival (OS) of 46.4 mo (47.5 mo median follow-up) in 68 pts with R/R MCL with a median of 3 (range, 1-5) prior LoT, including a BTKi (Goy et al. ASH 2023). Despite improvements in outcomes with BTKi therapy, pts with high-risk R/R MCL have poor outcomes and brexu-cel may provide benefit in earlier LoT (Bond, et al. J Clin Med. 2021). Here we report the primary analysis of ZUMA-2, Cohort 3, a global Phase 2 study to assess the safety and efficacy of brexu-cel in pts with BTKi-naive R/R MCL (NCT04880434).

Methods: Pts (≥18 y) underwent leukapheresis, optional prespecified bridging therapy, lymphodepleting chemotherapy, and 1 infusion of brexu-cel (2×10⁶ anti-CD19 CAR T cells/kg). The primary endpoint was ORR (CR + partial response [PR]) per the Lugano Classification (Cheson et al. J Clin Oncol. 2014) by independent radiology review committee (IRRC) assessment. The primary analysis was conducted after 86 pts were assessed for response 6 mo after the first objective response and was powered ≥90% to distinguish between an active therapy with ≥75% ORR and a therapy with ORR ≤57% (historical control) at a one-sided alpha level of 0.025. Key secondary endpoints were duration of response (DOR), best objective response (BOR), progression-free survival (PFS), OS, and safety.

Results: As of November 26, 2023, 95 pts were enrolled, 86 (91%) of whom were treated with brexu-cel; median follow-up was 15.5 mo (range, 1.4-27.1). At baseline (N=86), median age was 64 y (range, 40-82), 78% were male, 67% EU, 33% US, 73% had high or intermediate s-MIPI score, 47% had Ki-67 ≥30%, and 45% assessed (15/33) had a TP53 mutation. Median prior LoT was 1 (range, 1-5). Prior anti-CD20, anthracycline, and bendamustine therapies were received by 100%, 79%, and 27% of pts, respectively; 48% had prior autologous stem cell transplantation, and 36% received bridging therapy.

The primary endpoint was met with an ORR of 91% (95% CI, 82.5-95.9; P<.0001) per IRRC assessment; 73% (95% CI, 62.6-82.2) of pts had a CR, 17% (95% CI, 10.1-27.1) had a PR, 3% (95% CI, 0.7-9.9) had stable disease, and 3% (95% CI, 0.7-9.9) had progressive disease (PD) as best response to brexu-cel (2 pts not assessed). With 15.5-mo median follow-up, median (95% CI) DOR, PFS, and OS were 26.2 (17.4-not estimable [NE]; n=78), 27.1 (18.3-NE; N=86), and 27.1 mo (NE-NE; N=86), respectively. The 12-mo (95% CI) DOR, PFS, and OS rates were 80% (69.1-87.9), 75% (64.5-83.4), and 90% (80.7-94.4), respectively. At data cutoff, 73 pts (85%) were alive and 13 (15%) had died (no deaths occurred ≤30 days after brexu-cel infusion), 7 due to adverse events (AEs; 4 deemed unrelated to brexu-cel), 4 due to PD, and 2 due to other causes (sepsis [n=1] and failure to thrive after hip fracture [n=1]).

Most pts had at least 1 Grade (Gr) ≥3 brexu-cel–related AE (88%), 3 of which were Gr 5 AEs (due to JC virus PML on Day 303, polymicrobial infection on Day 69, and septic shock on Day 46). Gr ≥3 cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome, and neurological events occurred in 5 (6%), 18 (21%), and 23 pts (27%), respectively. Median (range) time to onset and duration of CRS events was 4 (1-12) and 6 days (1-36; n=82), respectively. Median (range) time to onset and duration of neurological events was 7 (1-373) and 8 days (1-179; n=67), respectively.

Median peak and area under the curve CAR T-cell levels were 77.2 cells/µL and 1021.2 cells/µL × days, respectively, and were positively correlated with Gr ≥3 neurologic events but not Gr ≥3 CRS.

Conclusions: In Cohort 3, brexu-cel demonstrated a high ORR (91%) and CR rate (73%) in pts with R/R MCL who were naive to BTKi, consistent with Cohort 1 of ZUMA-2 (BTKi-exposed pts). Efficacy was durable, with extended median DOR, PFS, and OS that translated to a 12-mo OS rate of 90%. Additionally, no new safety signals were detected, with a low rate of Gr ≥3 CRS and an expected rate of Gr ≥3 neurological events. These results support the continued use of brexu-cel in the R/R MCL setting, including pts naive to BTKi therapy.