Brexu-cel Elicits Sustained 3-Year Responses in Relapsed/Refractory MCL

Treatment with brexucabtagene autoleucel (brexu-cel; Tecartus; KTE-X19) drove durable responses in patients with relapsed/refractory mantle cell lymphoma (MCL), particularly those with minimal residual disease (MRD) negativity at 6 months, according to three-year findings from the phase 3 ZUMA-2 trial (NCT02601313) presented at the 2022 ASCO Annual Meeting.¹

At a median follow-up of 35.6 months (range, 25.9-56.3), the objective response rate (ORR) was 91% (95% CI, 81.8%-96.7%), with a complete response (CR) rate of 68% (95% CI, 55.2%-78.5%) in all treated patients (n = 68). In the intention-to-treat population (n = 74), the ORR was 84% (95% CI, 73.4%-91.3%), with a 62% CR rate (95% CI, 50.1%-73.2%).

Among patients who achieved CR or partial response (n = 62), the median duration of response (DOR) was 28.2 months (95% CI, 13.5-47.1). The median DOR was 46.7 months (95% CI, 24.8–not evaluable [NE]) among those who achieved only CR (n = 46).

“Collectively, these findings confirm the durable benefits of KTE-X19 and support future investigations of CD19-directed CAR T-cell therapy in patients with high-risk MCL in earlier treatment lines,” wrote lead study author Michael L. Wang, MD, of The University of Texas MD Anderson Cancer Center, and coauthors, in the poster.

In July 2020, the FDA approved brexu-cel, an autologous CD19-directed CAR T-cell therapy, for the treatment of patients with relapsed/refractory MCL based on findings from the ZUMA-2 trial.²

In the single-arm, open-label ZUMA-2 study, 74 patients were enrolled and leukapheresed, and 92% (n = 68) received a single infusion of brexu-cel at a dose of 2 x 10⁶ cells/kg.

To be eligible, patients had to have received between 1 and 5 lines of prior therapy, including anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 monoclonal antibody, and BTK inhibitor therapy.

Prior findings demonstrated that at a median follow-up of 17.5 months (range, 12.3-37.6), the ORR was 92% (95% CI, 82%-97%), and the CR rate was 67% (n = 40; 95% CI, 53%-78%) among the first 60 evaluable patients.³

Updated findings from the 3-year analysis indicated that the median overall survival (OS) among treated patients was 46.6 months (95% CI, 24.9-NE) and was not reached (95% CI, 37.5-NE) among those who achieved a CR. The 30-month OS rate among all treated patients was 60.3% (95% CI, 47.7%-70.8%). The median progression-free survival (PFS) was 25.8 months (95% CI, 9.6-47.6) and 48.0 months (95% CI, 25.8-NE), respectively. The 24-month PFS rate was 52.9% (95% CI, 39.9%-64.3%) among all treated patients.

At data cutoff, 37% of treated patients (n = 25/68) remained in response. Additionally late relapse beyond 24 months post-infusion was uncommon (n = 3).

An exploratory analysis of 19 patients evaluable for MRD at 6 months demonstrated a 100% ORR among 15 (79%) MRD-negative patients. At data cutoff, 60% of MRD-negative patients remained in response, with median DOR, PFS, and OS that had not been reached.

Notably, MRD negativity at months 1, 3, and 6 was associated with durable response, with 55%, 71%, and 69% of MRD-negative patients, respectively, in ongoing CR at data cutoff.

Additionally, analysis of MRD at months 3 and 6 was found to be predictive of relapse potential, with an area under the curve (AUC) of 0.80 and 0.75, respectively.

Among evaluable patients in ongoing response at months 18 and 24, B cells were detectable in 35% and 53%, and gene marked CAR T cells were detectable in 70% and 67%, respectively.

Brexu-cel also demonstrated potent activity regardless of bendamustine exposure (n = 37; 54%). The median time from last bendamustine exposure to brexu-cel was 20.9 months (range, 1.0-70.3).

However, peak and AUC CAR T-cell levels were significantly lower in patients with prior bendamustine exposure within 6 months of CAR T-cell infusion vs levels in patients without prior bendamustine exposure.

“Results of an exploratory post-hoc analysis suggest that bendamustine use shortly before leukapheresis requires careful consideration due to its potential effects on patient T-cell fitness and CAR T-cell expansion,” the authors wrote.

Regarding safety, no new signals were identified with longer follow-up. Since the primary analysis, only 3% of adverse effects (AEs) of interest on study had occurred. Grade 3 or greater serious AEs occurred in 7 patients (10%), including grade 3 encephalopathy (n = 1), grade 3 pneumonia and upper respiratory tract infection (n = 1), and grade 3 influenza (n = 1). Three new grade 5 AEs (n = 1, salmonella bacteremia; n = 2, secondary malignancies) occurred. No secondary malignancies or replication-competent retrovirus cases related to study treatment occurred at any time on study.

Further research into potential mechanisms of relapse is ongoing.

References

1. Wang ML, Munoz J, Goy A, et al. Three-year follow-up of outcomes with KTE-X19 in patients with relapsed/refractory mantle cell lymphoma in ZUMA-2. J Clin Oncol. 2022;40(suppl 16):7518. doi:10.1200/JCO.2022.40.16_suppl.7518
2. U.S. FDA Approves Kite’s Tecartus, the First and Only CAR T Treatment for Relapsed or Refractory Mantle Cell Lymphoma. News Release. Published July 24, 2020. Accessed September 13, 2022. https://bit.ly/2ZVy6v9
3. Wang ML, Munoz J, Goy A, et al. One-year follow-up of ZUMA-2, the multicenter, registrational study of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma. Presented at: 2021 EBMT Annual Meeting; March 14-17, 2021; virtual. Abstract OS19-4.