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Longest Follow-Up of CAR T-Cell Therapy in Mantle Cell Lymphoma Points Out to Long-Term Responses with Manageable Safety in Patients with Relapsed/Refractory Disease

Findings from a pivotal ZUMA-2 study support the investigation of CAR T-cell therapy in earlier lines of treatment
14 Jun 2022
Cancer Immunology and Immunotherapy;  Haematologic malignancies

After nearly a 3-year follow-up for patients with relapsed/refractory mantle cell lymphoma (MCL) in ZUMA-2 study, treatment with anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, brexucabtagene autoleucel (KTE-X19) showed durable responses and sustained survival with a manageable safety profile. These findings were also seen in patients within prespecified subgroups, such as those with high-risk characteristics or who received prior treatment. Durable outcomes suggest that the use of KTE-X19 in earlier lines of treatment may be beneficial for patients with relapsed/refractory MCL according to Dr. Michael Wang of The University of Texas MD Anderson Cancer Center in Houston, TX, US and colleagues who presented the findings at ASCO 2022 Annual Meeting along with a simultaneous publication on 4 June in the Journal of Clinical Oncology.

The authors wrote in the study background that despite recent therapeutic advances in MCL, most treatments provide limited duration of response (DoR), indicating high unmet need for novel treatments. In patients who discontinue the Bruton tyrosine kinase (BTK) inhibitor ibrutinib because of progressive disease or intolerance, the median overall survival (OS) ranges from 2.5 to 14.2 months. Prognosis in MCL depends on risk factors, with important high-risk factors including blastoid variant, high Ki-67 proliferation index, TP53 mutation or high P53 expression, and disease progression within 24 months after initial diagnosis. Patients with these characteristics have limited treatment options and poor outcomes, with a median OS of 6.6 months to 4 years after initial treatment. Moreover, treatments in previous lines may affect outcomes with subsequent treatments, e.g. bendamustine-containing treatments may be associated with reduced T-cell number and function.

ZUMA-2 is a pivotal, single-arm, multicentre, phase II study of the autologous anti-CD19 CAR T-cell therapy, brexucabtagene autoleucel in patients with heavily pretreated MCL that was relapsed/refractory to 1-5 prior treatment lines, including a BTK inhibitor ibrutinib or acalabrutinib. With a median follow-up of 12.3 months, the primary efficacy analysis demonstrated a 93% objective response rate (ORR) by an independent radiologic review committee, including a 67% complete response (CR) rate. Besed on these results, KTE-X19 was approved in the US and Europe for the treatment of adult patients with relapsed/refractory MCL.

In the latest article, the ZUMA-2 study team reported the long-term efficacy, safety, and pharmacology of KTE-X19 in patients with relapsed/refractory MCL with a median follow-up of 35.6 months. In addition, post hoc analyses of outcomes and the pharmacologic and pharmacodynamic profile of KTE-X19 in subgroups by prior bendamustine, prior BTK inhibitor exposure, and high-risk disease characteristics were reported.

In ZUMA-2, patients with relapsed/refractory MCL received a single infusion of KTE-X19 (2 × 106 CAR T cells/kg). After a median follow-up of 35.6 months, the ORR among all 68 treated patients was 91% (95% confidence interval [CI] 81.8 to 96.7) with 68% CRs (95% CI 55.2 to 78.5). Medians for DoR, progression-free survival, and OS were 28.2 months (95% CI 13.5 to 47.1), 25.8 months (95% CI 9.6 to 47.6), and 46.6 months (95% CI 24.9 to not estimable).

Post hoc analyses showed that ORRs and ongoing response rates were consistent among prespecified subgroups by prior BTK inhibitor exposure or high-risk characteristics. In an exploratory analysis, patients with prior bendamustine benefited from KTE-X19, but showed a trend toward attenuated T-cell functionality, with more impact of bendamustine given within 6 versus 12 months of leukapheresis.

Late-onset side effects were not frequent. Only 3% of treatment-emergent adverse events of interest in ZUMA-2 occurred during the longer follow-up period.

Translational assessments revealed associations with long-term benefits of KTE-X19 including high-peak CAR T-cell expansion in responders and the predictive value of minimal residual disease for relapse.

These longer-term ZUMA-2 data demonstrate that a single infusion of KTE-X19 resulted in high rates of durable responses in relapsed/refractory MCL across patients with high-risk disease characteristics, with manageable long-term safety. CAR T-cell levels persisted at varying levels through long-term follow-up, and this persistence was coupled with B-cell recovery in most patients. 

References

Wang M, Munoz J, Goy A, et al. Three-Year Follow-Up of KTE-X19 in Patients With Relapsed/Refractory Mantle Cell Lymphoma, Including High-Risk Subgroups, in the ZUMA-2 Study. JCO; Published online 4 June 2022. DOI: 10.1200/JCO.21.02370

Wang M, 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; abstr 7518).

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