A Retrospective Intra-Patient Analysis from ZUMA-5: Axicabtagene Ciloleucel (Axi-Cel) Compared with Prior Standard-of-Care Therapy in Patients with Relapsed/Refractory Follicular Lymphoma
Authors: Bachy Emmanuel , Neelapu Sattva S. , Chavez Julio C. , Yakoub-Agha Ibrahim , Lui Christine , Wulff Jacob , Miao Harry , Nikolajeva Olga , Best Timothy , Linot Camille , Jacobson Caron A. 
Published: December 2023

Introduction: Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, is approved for adults with relapsed/refractory (R/R) follicular lymphoma (FL). Approval was supported by ZUMA-5, a Phase 2, multicenter, single-arm study of axi-cel in patients with R/R indolent non-Hodgkin lymphoma. After a median of ≥3 years of follow-up in patients with FL, median duration of response was 38.6 months and 53% of patients were in ongoing response (Neelapu et al. ASH 2022. Abstract 4660). While responses were higher with axi-cel in ZUMA-5 compared with a matched standard-of-care (SOC) cohort (SCHOLAR-5), differences in patient characteristics between the groups limited comparison (Ghione et al. Blood. 2022). Here we report a retrospective, intra-patient assessment from the 4-year analysis of ZUMA-5 to evaluate the efficacy of axi-cel versus the most recent prior line of SOC therapy among patients with R/R FL.

Methods: The analysis included all patients with R/R FL who were enrolled and leukapheresed in ZUMA-5, and compared efficacy outcomes between axi-cel and a patient's most recent prior therapy (MRPT). Progression-free survival (PFS) after the MRPT was calculated from the date of therapy initiation to progression; those who did not have progression reported prior to leukapheresis were censored at leukapheresis. If multiple regimens were used in the same line, the earliest date of initiation and latest date of progression were used. Time to next therapy (TTNT) after the MRPT was calculated as the time from initiation of the MRPT to leukapheresis. For axi-cel, PFS was defined as time from leukapheresis to progression or death and TTNT was defined as time from leukapheresis to the start of subsequent anti-cancer therapy or death.

Results: A total of 127 patients with FL were enrolled in ZUMA-5 by the data cutoff date (March 31, 2023). Common MRPT regimens included anti-CD20 mAb-containing chemoimmunotherapy and PI3K inhibitors. A total of 46% of patients responded to their MRPT (27% complete response [CR] rate), while 53% had no response to MRPT (20% stable disease, 18% progression, and 14% unknown/not evaluable). In contrast, 94% of patients had an overall response to axi-cel (79% CR rate), and only 6% did not respond (2 stable disease, 2 progression, and 4 unknown/no disease). Among patients who responded to MRPT (n=59), 97% had a subsequent overall response to axi-cel (83% CR rate). Among those who did not respond to MRPT (n=67), 91% responded to axi-cel (76% CR rate).

Prior to leukapheresis, 83% of patients (106/127) had disease progression; median time between prior progression and leukapheresis was 1.4 months. Median PFS with MRPT was 9.4 months (95% CI, 7.5-11.9), while median PFS with subsequent axi-cel was substantially longer at 57.3 months (95% CI, 30.9-not estimable). In a subgroup analysis of those with ≥3 prior lines of therapy (n=80), medians of PFS with MRPT and axi-cel were 8.5 and 40.2 months, respectively. In all patients with FL, median TTNT with MRPT was 8.6 months (95% CI, 6.5-11.7) and median TTNT with axi-cel was 62.2 months (95% CI, 37.8-not estimable). Among patients who responded to MRPT, medians of PFS and TTNT after axi-cel were 62.2 months and 62.2 months, respectively, while those who did not respond to MRPT had medians of PFS and TTNT post axi-cel of 34.9 and 40.2 months, respectively. Among patients who had progression &lt;2 years after initial chemoimmunotherapy (POD24), the medians of PFS after MRPT and axi-cel were 7.4 and 57.3 months, respectively. Among those without POD24, the medians of PFS after MRPT and axi-cel were 12.0 and 48.6 months, respectively.

Conclusions: Through this retrospective analysis, axi-cel demonstrated robust improvement in median PFS and TTNT compared with the MRPT among patients with R/R FL in ZUMA-5, a population with substantial high-risk characteristics. Results support use of axi-cel earlier in the treatment paradigm for R/R FL.