Introduction: Brexu-cel is an autologous anti-CD19 CAR T-cell therapy approved for adults with R/R MCL in the US and after ≥2 prior lines of therapy (LoT) including a BTKi in the EU. In the pivotal ZUMA-2 Cohort 1 study, brexu-cel induced durable responses in pts with 1-5 prior LoT (median of 3) including a BTKi, with a median duration of response (DOR) and overall survival (OS) of 36.5 and 46.5 mo, respectively (median follow-up: 67.8 mo; Wang M. et al, ASH 2024). ZUMA-2 Cohort 3 is a Phase 2 study designed to assess the safety and efficacy of brexu-cel in pts with BTKi-naive R/R MCL (NCT04880434). In the primary analysis (PA), brexu-cel demonstrated a 91% objective response rate (ORR; P<.0001) and a 73% complete response (CR) rate after 15.5 mo of median follow-up in 86 pts with R/R MCL who were BTKi-naive (Meerten T. et al, ASH 2024). Here we report the 2-y update of ZUMA-2, Cohort 3.

Methods: Pts (≥18 y) underwent leukapheresis, optional bridging therapy, lymphodepleting chemotherapy, and infusion of brexu-cel (2×106anti-CD19 CAR T cells/kg). Pts had 1-5 prior LoT including chemotherapy and an anti-CD20 monoclonal antibody (excluding BTKi). The primary endpoint was ORR (CR + partial response) per Lugano Classification (Cheson et al. J Clin Oncol. 2014) by independent radiology review committee (IRRC). Key secondary endpoints were ORR per investigator review, DOR, progression-free survival (PFS), OS, and safety.

Results: As of November 26, 2024, median follow-up in 86 treated pts was 26.4 mo (range, 1.4-39.0). As reported in the PA, median age was 64 y (range, 40-82), 78% were male, and 91% were white. High-risk disease features were common: 73% had high or intermediate s-MIPI score, 65% had Ki-67 positivity ≥30%, and 65% had Stage IV disease. Most pts (79%) had 1 prior LoT with anthracycline and bendamustine received by 79% and 27% of pts, respectively; 48% had prior autologous stem cell transplantation (SCT), and 36% received bridging therapy.

The ORR per IRRC remained 91% (n=78; 95% CI, 82.5-95.9) with an updated CR rate of 79% (95% CI, 69.0-87.1). Per investigator, ORR and CR rates were 97% and 85% (94% and 87% concordance), respectively. Median DOR, PFS, and OS were not reached (NR). The 24-mo (95% CI) DOR, PFS, and OS rates were 75% (63.6-83.2; 81% for CR), 69% (58.0-77.8), and 84% (74.0-90.0), respectively. Of the 78 responders included in the DOR assessment, at data cutoff, 54 (69%) pts were censored for ongoing response without subsequent therapy or SCT, and 4 were censored for starting a new anti-cancer therapy; there were 14 (18%) progressive disease (PD) events and 6 (8%) death events. Ongoing response rates were similar across key subgroups including pts with high or intermediate s-MIPI scores, pts with Ki-67 IHC positivity ≥30%, and pts with advanced disease; however, notable differences were observed by prior LoT (69% for 1 vs 41% for 2-3) and prior bendamustine (43% for yes vs 70% for no).

At data cutoff, 69 pts (80%) were alive and 17 (20%) had died, 4 deaths occurred since the PA (all due to PD). Of the 17 deaths on study, 9 were due to PD and 8 were due to other reasons as previously reported (9% non-PD mortality rate). Since the PA, the proportion of pts with Grade (Gr) ≥3 brexu-cel–related adverse events (AEs) increased from 88% to 90% and increased from 23% to 30% for Gr ≥3 infections. Rates remained the same for Gr 5 AEs (9%), Gr ≥3 cytokine release syndrome (6%), and Gr≥3 neurological events (27%). Rates of any Gr and Gr ≥3 early (≤30 days of infusion) immune effector cell-associated hematotoxicity (ICAHT) were 90% and 14% and rates of any Gr and Gr ≥3 late (>30 days of infusion) ICAHT were 31% and 5%, respectively.

Medians for peak and area under the curve CAR T-cells were numerically higher in pts who had DOR of CR ≥6 mo (n=66) vs pts who had DOR of CR <6 mo (n=11), though not statistically significant.

Conclusions: After 2-y of median follow-up, IRRC-assessed ORR and CR rates were 91% and 79% with medians for DOR, PFS, and OS NR. Most responders were still in response with consistent ongoing response rates across most prespecified subgroups. Late onset toxicities were rare with no new Gr 5 events since the PA. These results suggest that brexu-cel may benefit pts in earlier LoT including some pts who are BTKi-naive with high-risk disease features, though the risk/benefit for each pt should be carefully assessed before determining salvage treatment.

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2025
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