Brexu-cel Generates Durable Responses and Survival Benefits in R/R B-ALL

Bijal Shah, MD

Adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) treated with brexucabtagene autoleucel (brexu-cel; Tecartus) had high rates of durable response, a promising overall survival (OS) rate, and a safety profile consistent with what has been previously observed with the the agent, according to 3-year follow-up results from the pivotal phase 3 ZUMA-3 trial (NCT02614066).¹

Included in this analysis with a longer follow-up were patients treated in the phase 2 portion of the ZUMA-3 study (n = 55) and a pooled analysis of patients with B-ALL who were treated in phase 1 and 2 with brexu-cel (n = 78).

The analysis showed that brexu-cel elicited a median OS of 26 months and demonstrated that responses remained durable in adults with a complete response (CR) plus CR with incomplete count recovery (CR+CRi) rate of 71%.

"Brexucabtagene autoleucel is a CD19 directed chimeric antigen receptor T-cell therapy engineered from a patients' own T-cells. It targets CD19 on the surface of B-cell acute lymphoblastic leukemia, leading to T-cell directed killing of these cancer cells. The therapy is currently FDA approved for adults with relapsed and refractory B-ALL," Bijal Shah, MD, investigator of ZUMA-3, and medical oncologist at Moffitt Cancer Center, Tampa, Florida, told Targeted Oncology^TM.

The ongoing, international, multicenter, phase 3 ZUMA-3 study is evaluating patients with B-ALL across sites in the United States, Canada, and Europe to determine the safety and efficacy of brexu-cel, a CD19-directed genetically modified autologous chimeric antigen receptor (CAR) T-cell immunotherapy.

Patients enrolled were aged 18 years and older with a diagnosis of relapsed/refractory ALL whose following standard systemic therapy or hematopoietic stem cell transplantation. Those enrolled were required to have bone marrow blasts greater than 5% and patients could have received prior blinatumomab and/or prior allogeneic stem cell transplant (alloSCT).

The primary end point of the study was the rate of overall CR or CR+CRi. Secondary end points included duration of remission (DOR), relapse-free survival (RFS), OS, minimal residual disease (MRD) negativity rate, and alloSCT rate.

Patients in ZUMA-3 underwent leukapheresis prior to getting cerebrospinal fluid prophylaxis and bridging chemotherapy. This was followed by conditioning chemotherapy with fludarabine at 25 mg/m² intravenously (IV) on days -4, -3, and -2, and cyclophosphamide at 900 mg/m² IV on day -2. Then, brexu-cel was administered at 1 x 10⁶ CD19-targeted CAR T cells/kg on day 0. All patients in the trial had a posttreatment assessment period and a long-term follow-up period.²

The majority of the patients included in the analysis were heavily pre-treated and had a median of 2 prior therapies, while 47% had received 3 or more prior therapies.

In the phase 2 cohort of patients treated with brexu-cel, (n=55) the median follow-up was 38.8 months (range, 32.7-44.6), and at 36.0 months, the OS rate was 47.1% (95% CI, 32.7-60.2). There was a median OS of 26.0 months among all treated patients in phase 2. Additionally, in patients with a CR+CRi (n=39), the OS was 38.9 months.

Overall CR+CRi, CR, and subsequent alloSCT rates did not change from the prior cutoff date, remaining at 71%, 56%, and 20%, respectively. For the median RFS censored and not censored at subsequent alloSCT, rates were 11.6 (2.7-20.5) and 11.7 months (2.8-20.5), respectively.

Then among all 78 patients treated with brexu-cel at the pivotal dose in phase 1 and 2 of the trial, the median follow-up was 41.6 months (range, 32.7-70.3). The median (95% CI) DOR censored and not censored at subsequent alloSCT was 18.6 (9.6-24.1) and 20.0 (10.3-24.1) months, respectively. For the median RFS, both censored and not censored at subsequent alloSCT rates were 11.7 (6.1-20.5) months.

Regarding safety, 36% of patients (n = 28) were still alive with a median OS of 25.6 months (95% CI, 16.2-47.0) at the data cutoff. Patients in the pooled analysis with grade 3 or greater AEs that were deemed treatment-related were unchanged since the prior data cutoff and there were no grade 5 AEs observed since that prior data cutoff.

“With two years of follow-up, responses remain durable. Although there was a numerical decrease in the response rate for those who had received blinatumomab prior to brexucabtagene, this failed to meet tests for statistical significance. Importantly, prior blinatumomab exposure did not impact the durability of response. This suggests that brexucabtagene remains an effective therapy for those with prior blinatumomab exposure, which is noteworthy, as ongoing trials increasingly support the integration of blinatumomab into the therapeutic regimen for newly diagnosed B-ALL patients," added Shah. "Those proceeding to brexucabtagene after only 1 line of prior therapy show high rates of response, few relapses, and high survival rates. These data have led to the development of new clinical trials in which brexucabtagene will be incorporated into the therapeutic regimen for those with newly diagnosed B-ALL.”

Additional data from subgroup analysis of the phase 3 ZUMA-3 trial were presented during the 2023 Transplantation & Cellular Therapy Meetings. Findings showed that treatment with brexu-cel produced a survival benefit in patients with relapsed/refractory B-ALL, regardless of prior lines of treatment, exposure to blinatumomab (Blincyto), or exposure to alloSCT.³

The overall CR rates were 90% and 67% when evaluating activity by 1 or 2 lines of prior therapy, respectively, and blast-free hypoplastic or aplastic bone marrow (BFBM) rates were 10% and 7%. A total of 20% of patients who had received at least 2 prior therapies did not respond to brexu-cel and all patients who did respond had at least 1 prior treatment.^2,3

For patients who had 1 and at least 2 prior lines of therapy, the DORs were 4.7 months (95% CI, 1.8-NE) and 14.6 months (9.4-NE), respectively. The median RFS was 5.6 months (95% CI, 0.0-NE) and 11.0 months (95% CI, 1.8-15.5) for these groups, and the median OS was not reached ([NR] 95% CI, 2.1-NE) and 25.4 months (95% CI, 14.2-NE), respectively.

Among those who were given prior blinatumomab, the overall CR rate was 60% compared with 80% for those who did not. The BFBM rates for these patients were 8% and 7%, respectively. A total of 24% of patients who had prior blinatumomab did not respond to brexu-cel vs 10% of patients who had not previously received the agent.

Patients who had received blinatumomab had median DOR, RFS, and OS rates of 19.1 months (95% CI, 1.3-NE), 11.6 months (95% CI, 0.0-25.4), and 14.2 months (3.2-26.0) compared with 10.3 months (95% CI, 5.2-NE), 11.7 months (95% CI, 2.8-22.1), respectively, and NR (18.6-NE) in those who did not have prior blinatumomab, respectively.

Moreover, the overall CR rate for patients who previously underwent alloSCT was 70% compared with 72% in those who did not receive transplant. These patients had BFBM rates of 9% and 6%, and 17% vs 16% of patients did not respond to brexu-cel. Among those who had prior alloSCT, the median DOR was 14.6 months (95% CI, 8.7-23.6) vs NR (95% CI, 4.7-NE) in those who did not. The median RFS was 11.7 months (95% CI, 0.0-20.5) and 6.1 months (95% CI, 2.2-NE) in the alloSCT and no-transplant groups, and the median OS was 25.4 months (95% CI, 14.2-NE) vs NR (95% CI, 9.0-NE), respectively.

“We are encouraged by the sustained benefit that a single one-time treatment of Tecartus continues to provide for patients living with this difficult-to-treat blood cancer,” said Frank Neumann, MD, PhD, SVP, Kite’s Global Head of Clinical Development. “Our hope is that these results, along with our commitment to long-term research of Tecartus, will continue to provide clarity to physicians on optimal treatment methods for these patients living with this rare disease who have suffered historically poor outcomes.”

"The role of allogeneic transplant following brexucabtagene remains undefined, and warrants further study," concluded Shah.

REFERENCES:

Kite’s Tecartus® CAR T-cell therapy demonstrates overall survival benefit in three-year follow-up of pivotal ZUMA-3 trial in relapsed/refractory B-cell acute lymphoblastic leukemia. News release. February 9, 2023. Accessed February 22, 2023. https://bit.ly/3So360L

Shah BD, Ghobadi A, Oluwole OO, et al.KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021;398(10299):491-502. doi:10.1016/S0140-6736(21)01222-8

Shah BD, Cassaday RD, Park JH, et al. Subgroup Analyses of Kte-X19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy, in Adult Patients (Pts) with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia (R/R B-ALL) in Zuma-3. Presented at: 2023 Transplantation & Cellular Therapy Meetings of ASCT and CIBMTR; February 15-19, 2023; Orlando, FL. Abstract 9