Updated long-term data with tisagenlecleucel confirm sustained benefit in patients with relapsed/refractory diffuse large B-cell lymphoma

Based on the pivotal JULIET trial, CAR-T cell therapy with tisagenlecleucel was registered for the treatment of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). ASH 2020 featured the presentation of updated long-term results of this study, with a median follow-up of 40 months. With this longer follow-up, the benefit of tisagenlecleucel was sustained in responding patients. In addition, biomarker analyses revealed that Myc overexpression and an unfavourable immunosuppressive tumour microenvironment, may impact CAR-T cell efficacy in patients with DLBCL.

Background

JULIET is a global, phase II trial of tisagenlecleucel (tisa-cel) in adult patients with DLBCL who have relapsed or are refractory to at least two prior lines of therapy. Previous reports of JULIET demonstrated that tisa-cel induces durable responses in adult patients with R/R DLBCL with a manageable safety profile. At ASH 2020, updated efficacy results with a 40.3-month median follow-up were presented. In addition, an analysis was performed to assess the association between treatment outcomes on tisa-cel and baseline Myc overexpression, or specific tumour microenvironment (TME) characteristics.

Results

The data cut-off for the presented analysis was February 20th 2020, corresponding with a median follow-up of 40.3 months. A total of 115 patients had received a tisa-cel infusion in the context of the JULIET trial. Updated efficacy results demonstrated a continued durable response with 24- and 36-month progression-free survival (PFS) rates of 33% and 31%, respectively. In total, 61 patients obtained a response, including 45 patients with a complete response and 16 patients obtaining a partial response. Among the responders, 60% were estimated to maintain that response at 24 and 36 months. Among patients who were in complete response at six months, 86% were estimated to maintain a response at 36 months. The median duration of response (DoR) was not reached. The median overall survival (OS) in all infused patients was 11.1 months (95%CI: 6.6-23.9 months) with a survival probability at 12, 24, and 36 months of 48.2%, 40.4%, and 36.2%, respectively. The medians for OS among patients with a CR (N=37) or PR (N=7) at three months were not yet reached. In total, 80% of patients in complete response had an OS of 20 months or longer. In this long-term follow-up analysis, no new adverse events were detected. Of the 23 patients with an ongoing complete response and an available B-cell count, eleven had CD19+ B-cells recovered back to normal after one year. Similar patterns were observed for CD20+ and CD22+ B-cells.

In addition to these updated results, Jaeger et al. also presented the outcome of a biomarker analysis that attempted to better define patients who may benefit most from CAR-T cell therapy with tisa-cel. In total, baseline archival tumour biopsies of 111 patients were tested for baseline Myc expression: 73 samples were found to be Myc positive (Myc+, defined as >40% by immunohistochemistry), while the remaining 38 samples were Myc negative (Myc-). Interestingly, a Myc- status was found to be associated with an improved treatment outcome on tisa-cel, compared to patients with Myc overexpression. In fact, by month six, 47% of Myc- patients were in CR/PR, while this was only the case for 25% of Myc+ patients. In addition, patients with baseline Myc- status also had a longer median DoR (not reached vs. 19 months, p=0.039), PFS (6.2 vs. 2.5 months, p=0.0093) and OS (21 vs. 7.8 months, p=0.12) compared to patients with Myc overexpression. A TME analysis of baseline biopsies further revealed that patients with low or no (cut-off of ≤ 3%) tumour infiltrating CD3+ T cells (N=16) had a worse outcome compared to patients with >3% CD3+ T cells (N=64). At six months, only 13% of patients with low or no tumour infiltrating CD3+ T cells in baseline biopsies responded to tisa-cel, as compared to 64% among patients with normal or high CD3+ T cells. In addition, patients with low or no tumour-infiltrating CD3+ T cells had shorter median DoR (p=0.25), PFS (2.2 vs. 4.2 months, p=0.022) and OS (7 vs. 21 months, p=0.032) compared to patients with normal or high CD3+ T cells.

Conclusions

Updated long-term data from the JULIET trial demonstrated durable responses, with a 24- and 36-month PFS of 33% and 31%, respectively. In addition, Myc overexpression was associated with worse outcome and an immunosuppressive TME with restricted T-cell response negatively affected CAR-T cell efficacy in patients with DLBCL. Nevertheless, further follow-up and increased sample size are needed to confirm these biomarker analyses. Overall, these updated results of the JULIET underscore the durability of the responses obtained with tisa-cel in patients with R/R DLBCL and further support the use of this CAR-T therapy in this setting. Also at ASH, results of the ELARA trial show that the potential of CAR-T cell therapy might not be restricted to patients with aggressive lymphoma by demonstrating high rates of durable responses in patients with R/R indolent lymphoma. As such, the place of CAR-T cell therapy in the lymphoma treatment paradigm is likely to expand further in the years to come.

Reference

Jaeger U, Bishop MR, Salles G, et al. Myc Expression and Tumor-Infiltrating T Cells Are Associated with Response in Patients (Pts) with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (r/r DLBCL) Treated with Tisagenlecleucel in the Juliet Trial. Presented at ASH 2020; Abstract 1194.