Axi-Cel Shows Durable Responses, Curative Hope in Non-Hodgkin Lymphoma

Axicabtagene ciloleucel (axi-cel; Yescarta) demonstrated profound and durable clinical benefits in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL), according to 5-year data from the phase 2 ZUMA-5 study (NCT03105336).

With a median follow-up of 64.6 months, axi-cel demonstrated sustained efficacy, with response rates consistent with earlier analyses and prolonged survival. The overall response rate (ORR) was 90%, with a complete response (CR) rate of 75%. The median progression-free survival (PFS) reached 62.2 months, and the median duration of response (DOR) was 60.4 months.

Significantly, neither median time to next treatment nor overall survival (OS) was reached, and 55% of patients were alive without needing subsequent anticancer therapy at the data cutoff.

For patients with follicular lymphoma (FL), analysis of lymphoma-specific survival revealed a plateau emerging after 30 months, suggesting axi-cel has the potential to be a curative therapy for this population.

Study Overview and Patient Population

The ZUMA-5 study was a phase 2, single-arm, multicenter trial designed to assess the long-term outcomes of axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with R/R iNHL. This analysis reports outcomes after a median follow-up of over 5 years.

Patients underwent leukapheresis, followed by lymphodepleting chemotherapy (fludarabine and cyclophosphamide), and a single infusion of axi-cel at a target dose of 2 x 10⁶ CAR T cells/kg. A total of 159 patients were enrolled, of whom 152 with iNHL received axi-cel. The cohort primarily consisted of patients with FL (n = 127) and marginal zone lymphoma (MZL, n = 31).

The primary end point was ORR, and secondary end points included CR rate, DOR, PFS, incidence of adverse events (AEs), OS, and time to next therapy.²

The patient population was heavily pretreated and presented with high-risk disease features, underscoring the significance of the observed long-term outcomes.¹

Lymphoma-Specific Survival and Curative Potential in Follicular Lymphoma

Due to the nature of iNHL, where competing risks (deaths unrelated to lymphoma) can affect standard PFS calculations, the study performed a lymphoma-specific survival analysis to more accurately assess the therapy's curative potential.

In patients with FL, the cumulative incidence of progression or death due to lymphoma or study treatment was 34%. A plateau in lymphoma-specific PFS began to emerge after 2 years, with only 2 such events occurring after month 30 post infusion.

This finding suggests that patients with FL who remain in remission beyond this point may be functionally cured. The 60-month rate of progression or lymphoma-specific death was 35.1%, while the rate of competing risks was 15.1%.

“In contrast to [diffuse large B-cell lymphoma], PFS with CAR T-cell therapies after 2 years of follow-up in R/R FL demonstrates a less obvious plateau, in part due to the long latency for the clinical manifestation of progression events and the deaths due to competing risks before progression, captured as PFS events even in patients who may be cured of their disease. Therefore, lymphoma-specific PFS may more accurately represent the curative potential of CAR T-cell therapy in FL,” the study authors wrote.

Long-Term Safety Profile

The 5-year analysis confirmed a manageable safety profile for axi-cel, with no new safety signals emerging since the 3-year follow-up. Late-onset toxicities were infrequent and largely determined to be unrelated to axi-cel. After the prior data cutoff, 1 serious AE considered related to axi-cel occurred: a grade 3 myelodysplastic syndrome. Six patients (4%) developed second primary malignancies, including acute leukemia. None were of T-cell origin. These were considered related to lymphodepleting chemotherapy and/or axi-cel.

A total of 46 patients (30%) died at any time during the study. Mortalities were evenly split between relapse-related and nonrelapse causes.

Biomarker and Correlative Insights

Correlative analyses provided insights into the factors associated with durable responses to axi-cel therapy. Robust early peak levels of CAR T cells in the blood were significantly associated with improved PFS in patients with both FL and MZL. In patients with FL, a higher frequency of naive T cells in the infused CAR T-cell product was associated with ongoing response and longer median PFS. Patients who remained in ongoing response had a naive T-cell frequency of 22.3% compared with 13.5% in those who relapsed and 9.0% in nonresponders.

A phase 3 randomized controlled trial, ZUMA-22 (NCT05371093), has been initiated to formally compare the benefit of axi-cel against standard-of-care therapies for R/R FL.

REFERENCES

1. Neelapu SS, Chavez JC, Sehgal AR, et al. Five-year follow-up analysis of ZUMA-5: axicabtagene ciloleucel in relapsed/refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2025;43(33):3573-3577. doi:10.1200/JCO-25-00668

2. A phase 2 multicenter study of axicabtagene ciloleucel in subjects with relapsed/​refractory indolent non-Hodgkin lymphoma (ZUMA-5). ClinicalTrials.gov. Updated January 6, 2025. Accessed November 25, 2025. https://www.clinicaltrials.gov/study/NCT03105336