Three-year follow-up of KTE-X19 in R/R mantle cell lymphoma: ZUMA-2 trial

Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell product, currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed/refractory (R/R) mantle cell lymphoma (MCL). ZUMA-2 (NCT02601313) is a phase II study of KTE-X19 in patients with heavily pretreated MCL. The Lymphoma Hub has previously reported on the study design and phase II results of the ZUMA-2 trial. Below, we provide a summary of the 3-year follow-up results as published by Wang, et al., in Journal of Clinical Oncology in 2022.¹

Study design

As previously reported, 74 patients were enrolled in the trial and 68 patients received treatment with KTE-X19. At the data cutoff, the median follow-up time was 35.6 months. Several high-risk sub-groups were present in the patient population, including patients with blastoid variant, high Ki-67 proliferation index, tumor protein p53 gene mutation16 or high p53 and disease progression within 24 months postdiagnosis. The primary endpoint was the objective response rate (ORR) assessed by independent radiologic review committee. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), adverse event (AE) incidence, blood CAR T-cell levels, and serum cytokine levels. Minimal residual disease (MRD) was assessed as an exploratory endpoint. Post-hoc assessment of subgroups was also performed based on prognostic features.¹

Results

Efficacy¹

• In the all-treated population, ORR was 91% (95% confidence interval [CI], 81.8–96.7). Further details on the complete response (CR) and partial response (PR) are presented in Figure 1.
  • Overall, 25 patients achieved CR or PR after initial stable disease
  • Median DOR was 28.2 months (46.7 months for CR and 2.2 months for PR)
  • At data cut-off, 37% of patients remained in ongoing response (all with CR)
  • Median PFS and OS were 25.8 months and 46.6 months, respectively
  • For those who achieved a CR, PR, and no response the median PFS was 48, 3.1, and 2.3 months, respectively

CR, complete response; ORR, objective response rate; PR, partial response.
*Adapted from Wang, et al.¹

At 6 months, 79% of MRD-assessable patients were MRD-negative (ORR, 100%). At the data cutoff, median DOR, PFS, and OS were 6.1, 7.1, and 27 months among the MRD-positive patients, respectively, and MRD negativity at months 3, 6, and 9 was associated with durable response.

In the intention-to-treat population, ORR was 84% (CR, 62%; PR, 22%) and median PFS and OS were 24 months and 47.4 months, respectively. Response rates were stable among prespecified subgroups of prior Bruton’s tyrosine kinase inhibitor exposure or high-risk characteristics. Blood CAR T-cell levels were higher at a median of 15 days post-infusion, with median concentrations plateauing at 0.19–0.34 cells/µL from Month 6–18.

Safety¹

No new safety signals were reported in the long-term follow-up of this trial, with only 3% of all adverse events of interest occurring since the previous data cutoff. AEs of any grade and ≥Grade 3 occurred in 26% and 21% of patients, respectively, and the most frequent AEs included cytopenia (19%), infections (10%), and neurologic events (3%).

Conclusion

This longer-term follow-up of ZUMA-2 study demonstrated the durable long-term effectiveness and safety of KTE-X19 in patients with R/R MCL. In addition, KTE-X19 showed positive responses in patients with high-risk characteristics, such as those with a high Ki-67 proliferation index. Taken together, these results further underline the benefits of KTE-X19 and support further investigations into this treatment protocol.