A Comparison of Overall Survival with Brexucabtagene Autoleucel (Brexu-cel) CAR T-Cell Therapy (ZUMA-2) and Standard of Care (SCHOLAR-2) in Patients with Relapsed/Refractory Mantle Cell Lymphoma (R/R MCL) Previously Treated with a Covalent Bruton Tyrosine Kinase Inhibitor (BTKi)

Introduction In the pre-chimeric antigen receptor [CAR] T-cell therapy era, patients with R/R MCL typically faced a poor prognosis after failing BTKi with no established standard of care (SOC). In a phase 2, multicenter, single-arm trial (ZUMA-2; NCT02601313), brexu-cel demonstrated long-term overall survival (OS) benefit in patients with R/R MCL who had 1–5 prior therapies, including a BTKi (Wang et al. JCO 2022). The European retrospective observational study, SCHOLAR-2, showed poor OS in 288 patients with R/R MCL who failed a BTKi due to disease progression or intolerance (Hess et al. BJH 2023). SCHOLAR-2 data reflects clinical practice (excluding CAR T-cell therapies), providing a benchmark for indirect treatment comparisons (ITCs) of brexu-cel to historical SOC. We present results of an updated ITC of OS of brexu-cel versus non-CAR T-cell SOC using individual patient data from ZUMA-2 and SCHOLAR-2. Methods Long-term follow-up data from ZUMA-2 were used for brexu-cel (data cut-off: July 23, 2022). Real-world evidence on the effectiveness of non-CAR T-cell SOC was from the subset of the SCHOLAR-2 post-BTKi treated population that better resembled patients in ZUMA-2 (i.e., ECOG performance status 0–1 and ≥1 year of follow-up). Comparisons of OS were made using three different statistical methods which adjusted for imbalances in pre-specified key prognostic factors between the study populations: 1) inverse probability weighting (IPW) with ZUMA-2 as the target population, 2) multivariable regression (MVR), and 3) doubly robust (DR). Variables included in the final models are in Table 1. Relative treatment effects were shown as hazard ratios (HRs) with 95% confidence intervals (CIs). Results Median follow-up times were 46.1 and 27.6 months for ZUMA-2 and SCHOLAR-2 cohort, respectively. At baseline, the study populations were well balanced (i.e., absolute standardized difference <10%) in terms of prior BTKi duration/response, while other characteristics were imbalanced (Table 1); after weighting in the base-case analysis (IPW approach), all the key prognostic factors were well-balanced between the two populations.Median OS was 46.4 months (95% CI: 24.9–58.7) with brexu-cel and 15.4 months (95% CI: 9.99–30.9) with non-CAR T-cell SOC. The IPW-adjusted median OS with non-CAR T-cell SOC was 14.0 months (95% CI: 6.8–30.9). Brexu-cel was associated with improved OS compared to non-CAR T-cell SOC in the unadjusted and adjusted comparisons (Figure 1). The adjusted HRs were 0.38 (95% CI: 0.24–0.62; p<0.001) for IPW, 0.46 (95% CI: 0.28–0.74; p=0.001) for MVR, and 0.38 (95% CI: 0.24–0.60; p<0.001) for DR. Conclusion/Summary Despite the inherent limitations of an unanchored ITC, these updated results continue to suggest significant OS benefit with brexu-cel versus non-CAR T-cell SOC in patients with R/R MCL post-BTKi and may help inform treatment choices in this high unmet need population.