Five Years In, Axi-Cel Proves Resilience as Relapsed and Refractory iNHL Treatment

After five years of follow-up in the phase 2 ZUMA-5 clinical trial, axicabtagene ciloleucel (axi-cel) continues to induce durable responses and long-term survival for patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL).¹

Results from the 5-year follow-up analysis of ZUMA-5 presented at the 66th American Society of Hematology Annual Meeting & Exposition also showed no new safety signals with axi-cel. Moreover, more than 50% of the study population was alive at the time of data cutoff with no subsequent therapy needed.

“We previously showed that axi-cel was highly effective in r/r indolent B-cell non-Hodgkin lymphoma with an overall response rate of 90% and a complete response [CR] rate of 75%. However, it was unclear whether axi-cel was potentially curative for these lymphomas,” Sattva S. Neelapu, MD, told Blood Cancers Today. “In the 5-year analysis, we found that the median PFS and overall survival were not reached after 5 years of follow-up. Importantly, only 4 patients progressed beyond 2 years, and we observed a plateau in the lymphoma-specific PFS curve after about 2 years. The efficacy was consistent regardless of high-risk factors in follicular lymphoma patients.”

Two iNHL subgroups were evaluated in ZUMA-5, including patients with follicular lymphoma (FL, n=127) and those with marginal zone lymphoma (n=31). The patients received axi-cel after two or more lines of therapy, including an anti-CD20 monoclonal antibody plus an alkylating agent. Per the ZUMA-5 protocol, these patients received axi-cel (dose, 2 × 10⁶ chimeric antigen receptor T cells/kg). The primary endpoint of overall response rate (ORR) was previously reported. The secondary endpoint was time to event outcome per investigator assessment. Lymphoma-specific survival and identification of covariates associated with ongoing response were exploratory endpoints.

At a median age of 64.6 months (range, 32.3–81.4), the median duration of response was 60.4 months (95% CI, 43.9-62.0). Notably, 58% of patients achieved a complete response with axi-cel. Overall, 50.4% of patients reached the 60-month milestone.

The median progression-free survival (PFS) among partial responders was 62.2 months (95% CI, 34.9-not evaluable [NE]). In the patients with a partial response, the median PFS was 6.9 months (95%. CI, 4.5-12.4). At the 60-month timepoint, PFS rates in the FL cohort were consistent despite high-risk characteristics in some patients. The median overall survival (OS) with axi-cel was not reached (95% CI, NE-NE). At 60 months, the estimated OS rate was 69.0% (95% CI, 60.8-75.8).

The median time to next therapy was not reached in either cohort (95% CI, 38.6-NE). Fifty-five percent of patients remain alive with no anticancer therapy at the time of data cutoff.

Exploratory analysis results revealed a 60-month cumulative incidence of progression or lymphoma-specific death of 35.1% and 15.1% cumulative incidence of non–lymphoma-specific deaths. Furthermore, there was a 15.6% cumulative incidence of lymphoma-specific death at 60 months, with non–lymphoma-specific death occurring in 15.6% of patients.

After the 4-year analysis, investigators discovered three new safety events unrelated to axi-cel, including grade 3 metastasis, grade 1 bladder cancer, and grade 4 myelodysplastic syndrome. There was one patient death due to pneumonia, which was unrelated to axi-cel. Overall, there were 14 deaths due to disease progression in the study, six resulting from secondary malignancies, 15 due to infections, and 12 deaths from unknown causes.

“Patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma including FL and MZL have a median PFS) of only 12-18 months with currently available therapies in the third-line setting and beyond. Moreover, repeated treatment with chemotherapy can increase the risk of therapy-related myeloid neoplasms. Existing therapies are also not known to be curative for indolent non-Hodgkin lymphoma,” said Dr. Neelapu, professor and deputy department chair, Department of Lymphoma/Myeloma, Division of Cancer Medicines, The University of Texas MD Anderson Cancer Center.

“As opposed to other available therapies that are given over a period of months to years, axi-cel therapy on the ZUMA-5 trial requires only a one-time infusion,” Neelapu added. “These results demonstrate that axi-cel has the longest median PFS compared to any other available therapy for patients with relapsed or refractory FL. Moreover, axi-cel now offers patients a potentially curative treatment option for these indolent B-cell lymphomas, which was previously not possible to achieve with conventional therapies including chemotherapy, immunotherapy, and targeted therapies.”

Reference

Neelapu S, Chavez J, Sehgal A. et al. 5-year follow-up analysis from Zuma-5: a phase 2 trial of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory indolent non-Hodgkin lymphoma. Abstract 864. Presented at the 66th American Society of Hematology Annual Meeting; December 7-10, 2024; San Diego, California.