Indirect Treatment Comparison Indicates Improved OS With Brexu-Cel in BTK Inhibitor–Exposed R/R MCL

Brexucabtagene autoleucel (Brexu-cel; Tecartus) demonstrated an improvement in overall survival (OS) vs standard of care (SOC) therapy in patients with relapsed/refractory mantle cell lymphoma (MCL) following prior exposure to a BTK inhibitor, according to data from an indirect treatment comparison of findings from the phase 2 ZUMA-2 trial (NCT02601313) and retrospective SCHOLAR-2 trial published in Leukemia & Lymphoma.¹

At a median follow-up of 35.8 months (95% CI, 34.0-49.8) for the ZUMA-2 cohort and 27.6 months (95% CI, 21.9-38.7) for the SCHOLAR-2 cohort, median OS was 46.6 months with brexu-cel vs 15.4 months with SOC. Both the unadjusted and adjusted analyses for OS demonstrated that brexu-cel was superior to SOC (unadjusted HR, 0.42; 95% CI, 0.26-0.68; P < .001; adjusted HR, 0.38; 95% CI, 0.23-0.61; P < .001).

“Results from this comparative analysis of ZUMA-2 and SCHOLAR-2 patients with similar clinical profiles receiving non–CAR T-cell SOC [standard of care] in routine clinical settings suggest a survival benefit with brexu-cel over SOC, which supplement the findings of the single-arm ZUMA-2 trial,” lead study author Georg Hess, MD, associate professor in the Department of Hematology at the Johannes Gutenberg University in Mainz, Germany, and coauthors wrote in the publication.

The pivotal, single-arm, phase 2 ZUMA-2 trial enrolled patients at least 18 years of age with histologically confirmed MCL following no more than 5 prior lines of therapy, including an anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 monoclonal antibody, and BTK inhibitor therapy.² For comparison, investigators compiled data on 60 patients from the retrospective SCHOLAR-2 chart review that better resembled those treated on ZUMA-2. Patients were at least 18 years of age with MCL that had progressed on BTK inhibitor therapy or were intolerant to BTK inhibitor therapy.³ Patients in both cohorts had an ECOG performance status of 0 or 1, and those with prior exposure to CAR T-cell therapy or another genetically modified T-cell therapy and a history or presence of central nervous system disorders were excluded.

Based on data availability and clinical input, 4 variables were identified as key prognostic factors and/or effect modifiers that needed to be balanced between populations prior to conducting the indirect comparison. These included response to prior BTK inhibitor therapy, duration on prior BTK inhibitor therapy, number of prior lines of therapy, and prior autologous stem cell transplantation. The following clinically relevant potential cofounders for OS were also considered for inclusion in the model to better balance the initial 4 variables: age, sex, disease staging, and ECOG performance status.

In accordance with the National Institute for Health and Care Excellence guidance, inverse probability weighting (IPW) with ZUMA-2 as the target population, regression adjustment (RA) using a multivariable regression model, and doubly robust (DR) methods were used to adjust for differences in baseline characteristics across the two cohorts.

Additional findings from the study indicated that the alternative IPW models also showed improved OS with brexu-cel, with hazard ratios of 0.38 (95% CI, 0.21-0.68) with the IPW-SA MI model and 0.46 (95% CI, 0.25-0.83) with the IPW-SA full model.

Similar results were seen from the RA and DR analyses, with hazard ratios of 0.45 (95% CI, 0.28-0.74) and 0.37 (95% CI, 0.23-0.59), respectively.

“Given the number of assumptions and limitations around covariate adjustment and the modest SCHOLAR-2 cohort sample size, results should be interpreted with caution; nevertheless, our findings suggest that brexu-cel can help address the significant lack of effective treatments for patients with relapsed/refractory MCL who have previously received a covalent BTK inhibitor therapy,” study authors wrote in conclusion.

References

1. Hess G, Dreyling M, Oberic L, et al. Indirect treatment comparison of brexucabtagene autoleucel (ZUMA-2) versus standard of care (SCHOLAR-2) in relapsed/refractory mantle cell lymphoma. Leuk Lymphoma. 2023;16:1-12. doi:10.1080/10428194.2023.2268228
2. 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. J Clin Oncol. 2023;41(3):555-567. doi:10.1200/JCO.21.02370
3. Hess G, Dreyling M, Oberic L, et al. Real-world experience among patients with relapsed/refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor failure in Europe: the SCHOLAR-2 retrospective chart review study. Br J Haematol. 2023;202(4):749-759. doi:10.1111/bjh.18519