Updated Outcomes from the Historical Control Study SCHOLAR-3 Contextualizing ZUMA-3 Results of Brexucabtagene Autoleucel (KTE-X19) in Adult Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia (R/R B-ALL)

Introduction: Brexucabtagene autoleucel (brexu-cel, formerly known as KTE-X19) 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 B-ALL based on the results of the pivotal Phase 2 ZUMA-3 study. After 2 years of follow-up in ZUMA-3, brexu-cel demonstrated a high overall complete remission (CR) rate (CR + CR with incomplete hematologic recovery [CRi]) of 71%, with a median relapse-free survival (RFS; censored at subsequent stem cell transplant [SCT]) of 11.6 months and a median overall survival (OS) of 25.4 months in 55 treated adults with R/R B-ALL (Shah et al, ASCO 2022). To better assess the unmet need and the benefit of brexu-cel in adults with R/R B-ALL, the retrospective historical control study SCHOLAR-3 was conducted (Shah et al, ASH 2021). Here, we report updated outcomes in SCHOLAR-3 with longer follow-up.

Methods: In ZUMA-3 (NCT02614066), patients (≥18 years) with R/R B-ALL received a single infusion of brexu-cel (1×10⁶ CAR T cells/kg) following leukapheresis and conditioning chemotherapy (Shah et al, Lancet 2021). Detailed SCHOLAR-3 methodology was previously reported (Shah et al, ASH 2021). Briefly, propensity scoring was used to match ZUMA-3 treated patients with adult patients with R/R B‑ALL treated in historical clinical trials (synthetic control arm [SCA]) based on key baseline characteristics and prior therapies. The study consisted of 3 patient-matched historical control cohorts: (1) SCA-1: patients who were previously naive to blinatumomab and inotuzumab prior to enrollment to the historical clinical trial; (2) SCA-2: patients who were previously treated with blinatumomab or inotuzumab prior to enrollment to the historical clinical trial; and (3) SCA-combined: SCA-1 and SCA-2 combined data set (Figure). These cohorts were compared with matched ZUMA-3 patients who were previously naive to blinatumomab and inotuzumab prior to enrollment in ZUMA-3, previously treated with blinatumomab or inotuzumab prior to enrollment in ZUMA-3, and any pretreatment status, respectively (Figure). The primary endpoints were CR/CRi rate at 24 weeks for patients previously naive to blinatumomab and inotuzumab and OS for all cohorts.

Results: At data cutoff, the median follow-up time for the SCHOLAR-3 analysis was 18.6 months. Baseline characteristics were previously reported (Shah et al, ASH 2021). For patients previously naive to blinatumomab and inotuzumab in ZUMA-3 (n=20) vs SCA-1 (n=20), the CR/CRi rates at 24 weeks were 85% (95% CI, 62.1-96.8) vs 35% (95% CI, 15.4-59.2; P=.0031); the medians for RFS were 20.5 (2.8-not evaluable [NE]) vs 0.03 months (95% CI, 0.0-4.6; HR, 0.18 [95% CI, 0.1-0.5]; P=.0004); and the medians for OS were not reached (95% CI, 18.2-NE) vs 5.5 months (95% CI, 1.9-12.1; HR, 0.15 [95% CI, 0.1-0.5]; P=.0001), respectively (Table). The allogeneic stem cell transplantation rates were 35% (95% CI, 15.4-59.2) vs 20% (95% CI, 5.7-43.7; P=.4801) for ZUMA-3 and SCA-1, respectively (Table).

For patients previously treated with blinatumomab or inotuzumab in ZUMA-3 (n=29) vs SCA-2 (n=20), the median OS was 15.9 (95% CI, 3.2-26.0) vs 4.8 months (95% CI, 2.7-12.4; HR, 0.55 [95% CI, 0.3-1.1]), respectively. In ZUMA-3 (n=49) vs SCA-combined (n=40), the median OS was 25.5 (95% CI, 15.9-NE) vs 5.5 months (95% CI, 3.3-9.2; HR, 0.32 [0.2-0.6]; P=.0001), respectively. For the intention-to-treat analysis, the median OS for all matched ZUMA-3 patients (N=65) was 23.1 (95% CI, 9.9-NE) and 6.0 months (95% CI, 4.2-7.3) for all matched SCA patients (N=65; HR, 0.47 [95% CI, 0.3-0.8]; P=.0011).

Conclusions: Outcomes of patients treated in historical standard-of-care trials were poor regardless of prior therapy status (blinatumomab/inotuzumab-treated or -naive), with a median OS of less than 6 months. In contrast, matched ZUMA-3 patients achieved a median OS of >25 months, more than 4 times that of the SCA arm, highlighting a considerable benefit of KTE-X19 over standard-of-care therapies in this patient population. These results suggest that brexu-cel may improve outcomes compared to historical standard-of-care therapies and helps to address an unmet need for patients with R/R B-ALL.