Axi-cel Shows Better Outcomes When Given After Corticosteroids in R/R LBCL

Administering corticosteroids prior to chimeric antigen receptor (CAR) T-cell therapy with axicabtagene ciloleucel (axi-cel; Yescarta) in adult patients with relapsed or refractory large B-cell lymphoma (LBCL) may positively impact the benefit/risk profile of axi-cel treatment, according to findings for cohort 6 of the phase 2 ZUMA-1 study (NCT02348216).¹

Patients in cohort 6 of ZUMA-1 are part of the safety management portion of the study, during which investigators assess how the use of prophylactic regimens or earlier interventions impact the incidence and severity of cytokine release syndrome (CRS) as well as neurologic toxicities. As secondary end points, the safety management portion of ZUMA-1 is also evaluating changes in quality of life over time according to the European Quality of Life Five Dimension Five Level Scale, and changes over time according to the Visual Analogue Scale score.

The target dose of CAR T cells in the study is 2 x 10⁶. Patients also received conditioning chemotherapy of fludarabine and cyclophosphamide and dexamethasone 10 mg orally on day 0 before axi‑cel, as well as day 1 and 2. For developing CRS or neurotoxicity, patients also received earlier intervention with steroids and tocilizumab.

The use of corticosteroids prior to CAR T cells did in fact reduce the rate of severe CRS and neurologic toxicities. This strategy also appeared to delay the onset of CRS in patients but did not have any bearing on the median peak CAR T-cell levels or responses to axi-cel.²

Overall, the analysis of cohort 6 included 40 patients with relapsed/refractory LBCL who were followed for a median of 8.9 months. Compared with cohorts 1 and 2, which both received less corticosteroid intervention, there were no cases of grade ≥3 CRS in cohort 6, and only 13% of patients had grade ≥3 neurologic toxicities. No grade 5 events of either CRS or neurologic toxicities were observed in cohort 6. Additionally, receipt of corticosteroids prior to axi-cel appeared to delay the onset of CRS by a median of 5 days compared with 2 days for combined cohorts 1 and 2 as well as in cohort 4, which allowed for earlier but prophylactic use of steroids. Sixty-eight percent of patients in cohort 6 did not experience neurologic toxicities or CRS within 72 hours of receiving axi-cel in the study.

In terms of efficacy, the objective response rate achieved with corticosteroids before axi-cel was 95% with complete responses in 80% of patients. Responses were ongoing at data cutoff for 63% of patients in the cohort. This was compared with the objective response rate of 82% and complete response rate of 54%, as seen in the combined cohorts 1 and 2.

Further, cohort 6 saw higher median peak CAR T-cell levels compared with cohorts 1, 2, and 4. The median was 64 cells/µL in cohort 6 versus 42 cells/µL in combined cohorts 1 and 2, and 53 cells/µL in cohort 4. The median CAR AUC in blood confirmed the median peak CAR T cell levels observed in all cohorts, which was 526 cells/µL × day for cohort 6 compared with 462 cells/µL × day for cohorts 1 and 2, and 511 cells/µL × day for cohort 4. Finally, patients in cohort 6 had lower median peak serum levels of biomarkers associated with CAR T-cell treatment-related adverse events compared with cohorts 1, 2, and 4.

The ZUMA-1 trial is a multicenter study that is investigating both the safety and efficacy of axi-cel as treatment of adult patients with refractory aggressive non-Hodgkin lymphoma. For the analysis of cohort 6, baseline data showed that the median age was 64 years, and most patients were male (58%) with an ECOG performance status of 1 (55%). Sixty-five percent of patients had stage III/IV disease and 53% received bridging therapy. In cohort 6, the median tumor burden was lower than that observed in cohorts 1, 2, and 4 at 1184 mm versus 3723 mm² for cohorts 1 and 2, and 2100 mm² for cohort 4. The median lactate dehydrogenase level at baseline was similar in C6 and C4 at 236 U/L and 262 U/L, respectively, compared to the lower level of 356 U/L observed in cohorts 1 and 2.

This cohort analysis suggests that the higher rate of CRS and neurologic events of 13% and 28%, respectively, observed with axi-cel in the primary analysis can be improved upon with prophylactic steroid use. Investigators suggest longer follow-up to determine how use of corticosteroids prior to axi-cel may impact responses and survival.

_References:

_{1. KITE announces new ZUMA-1 cohort analysis evaluating prophylactic corticosteroid use with Yescarta® in patients with relapsed or refractory large b-cell lymphoma. News release. Kite Pharamceuticals. February 10, 2021. Accessed March 22, 2021. https://bit.ly/3sepP15}

_{2. Oluwole OO, Munoz J, Vose JM, et al. Prophylactic Steroid Use with axicabtagene ciloleucel in patients with relapsed/refractory large b-cell lymphoma. Presented at: 2021 Transplantation and Cellular Therapy Meetings; February 8-12, 2021; Virtual. Abstract 70.}