Axi-cel Maintains PFS and ORR Benefit in 3-Year Follow-Up of ZUMA-5 in Indolent NHL

Axicabtagene ciloleucel (axi-cel; Yescarta) continued to elicit improved progression-free survival (PFS) and overall response rates (ORR) in patients with relapsed/refractory indolent non-Hodgkin lymphoma (iNHL), according to data from the 3-year follow-up of the phase 2 ZUMA-5 trial (NCT03105336) presented during the 2022 ASH Annual Meeting.¹

The updated efficacy analysis evaluated 159 patients in an intention-to-treat analysis following a minimum of 3 years of follow-up. After a median follow-up of 40.5 months (range, 8.3-57.4), the ORR across all patients with iNHL was 90% (95% CI, 84%-94%) and the complete response rate (CR) was 75%.

Additionally, the median follow-up for patients with follicular lymphoma (n = 127) and marginal zone lymphoma (n = 31) was 41.7 months (range, 32.7-57.4) and 31.8 months (range, 8.3-52.3), respectively. The ORR rate of those with follicular lymphoma was 94% and the CR was 79%; those with marginal zone lymphoma had an ORR of 77% and a 65% CR rate.

The median duration of response (DOR) was 38.6 months (95% CI, 33.1-not evaluable [NE]) across all patients with iNHL, though the median DOR was not reached (NR; 95% CI, 13.4-NE) in patients with marginal zone lymphoma or those who achieved CR. The median time to next treatment was NR (95% CI, 35.5-NE) across both disease types.

The use of axi-cel led to an extended median PFS with longer follow-up and was 40.2 months (95% CI, 28.9-NE) across all patients, though it was NR (95% CI, 12.4-NE) in patients with marginal zone lymphoma. Median overall survival (OS) was NR (95% CI, NE-NE) across both disease types. 

The 36-month PFS rates were 54.4% (95% CI, 44.2%-63.5%) and 56.2% (95% CI, 34.8%-73.1%) for patients with follicular lymphoma and marginal zone lymphoma, respectively. Additionally, the 36-month OS rates were 75.5% (95% CI, 66.9%-82.2%) and 73.8% (95% CI, 52.7%-86.6%), respectively.

“We reported the updated clinical and pharmacological outcomes from ZUMA-5 with more than three years of follow-up,” lead study author, Sattva S. Neelapu, MD, the deputy department chair and a professor in the Department of Lymphoma/Myeloma, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, said in a presentation of the data, adding that, “Axi-cel continued to induce durable responses and improve survival outcomes in patients with relapsed/refractory iNHL.” 

Previous data from the ZUMA-5 trial, which evaluated the efficacy and safety of axi-cel in patients with relapsed/refractory iNHL, resulted in high response rates and improved survival. In March 2021, prior findings from the phase 2, multicenter, single-arm trial led to the FDA approval of axi-cel for adult patients with relapsed/refractory follicular lymphoma following 2 or more lines of systemic therapy.²

To be eligible for enrollment, adult patients must have had relapsed/refractory grade 1 to 3a follicular lymphoma or marginal zone lymphoma, either nodal or extranodal. Additionally, patients must have undergone at least 2 prior lines of therapy, including an anti-CD20 monoclonal antibody in combination with an alkylating agent.

Once enrolled, eligible patients were given lymphodepleting chemotherapy with 30 mg/m2 of intravenous (IV) fludarabine and 500 mg/m2 of IV cyclophosphamide on days -5, -4, and -3. This was followed by axi-cel infusion on day 0 consisting of 2 × 106 CAR+ cells/kg.

The primary end point of the study was ORR; secondary end points included CR rate, DOR, PFS, OS, safety, and CAR T-cell and cytokine levels.

“Patients with follicular lymphoma who had other high-risk baseline characteristics had consistent PFS rates at 36 months with the overall population. Of note, those who did not have prior bendamustine appear to have a higher PFS rate than those who did have prior bendamustine,” Neelapu explained.

Moreover, an exploratory analysis of lymphoma-specific survival was performed. Lymphoma-specific survival end points were not reached across any subgroups, leading to a delayed plateau in later months.

Regarding safety, patients with follicular lymphoma included in the safety population (n = 124) experienced any-grade and grade 3 or greater adverse effects (AEs) at a rate of 6% and 4%, respectively. Serious any-grade and grade 3 or greater AEs both occurred in 4% of patients.

Safety-evaluable patients with marginal zone lymphoma (n = 28) experienced any-grade and grade 3 or greater AEs at a rate of 32% and 21%, respectively. Serious any-grade and grade 3 or greater AEs occurred in 11% and 7% of patients, respectively.

AEs largely occurred in patients with marginal zone lymphoma who were recently enrolled. No new cases of grade 3 or higher hypogammaglobulinemia or axi-cel-related secondary malignancies were reported following the data cutoff for the primary analysis in March 2020.

However, 10 additional patients died since the 2-year analysis due to progression (n = 1), malignancies (n = 3), and other causes not related to axi-cel (n = 6). No new safety signals were observed with the agent.

Additionally, patients with follicular lymphoma who had relapsed following axi-cel infusion were more likely to have elevated pre-infusion inflammatory markers and a high Follicular Lymphoma Interntional Prognostic Index score, as well as elevated levels of CCL17, CCL22, TNF alpha, and IL-16 were all associated with a negative PFS in patients with follicular lymphoma.

“Longer follow-up is needed to determine whether the emergence of [the] plateau in lymphoma-specific PFS will be maintained,” Neelapu concluded, adding that, “These data further support axi-cel as a highly effective therapeutic approach for patients with relapsed/refractory iNHL.”

References

1. Neelapu SS, Chavez J, Sehgal AR, et al. 3-Year follow-up analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory (r/r) indolent non-Hodgkin lymphoma (iNHL). Blood. 2022;140(suppl 1):10380-10383. doi:10.1182/blood-2022-156120.
2. US FDA approves Yescarta for relapsed or refractory follicular lymphoma after two or more lines of systemic therapy. News release. Kite. March 05, 2021. Accessed December 14, 2022. http://bit.ly/3kOyKnb