Axi-Cel Demonstrates Ongoing Survival Benefit in Relapsed/Refractory iNHL

Sattva S. Neelapu, MD

Axicabtagene ciloleucel (axi-cel; Yescarta) induced high response rates and improved survival in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma (MZL), according to updated data from the phase 2 ZUMA-5 trial (NCT03105336) presented at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition.

Among efficacy-evaluable treated patients with indolent non-Hodgkin lymphomas (iNHLs) in the trial (n = 110), the median overall survival (OS) was not reached and the 24-month OS was 79.1%.¹

The results showed that the 24-month OS was 81.2% (95% CI, 71.2%-88.1%) in the follicular lymphoma group and 69.9% (95% CI, 44.0%85.5%) in the MZL group.

“Overall, these results indicate that axi-cel is a highly effective therapeutic approach for patients with relapsed/refractory iNHL,” said Sattva S. Neelapu, MD, deputy director of the lymphoma/myeloma department at The University of Texas MD Anderson Cancer Center in Houston, Texas. He presented the findings and added that axi-cel “demonstrates substantial and continued benefit” in this patient population.

As of the March 31, 2021, data cut-off, the median follow-up in the follicular lymphoma group and in the MZL group was 30.9 months (range, 24.7-44.3) and 23.8 months in the MZL group (range, 7.4-39.4).

The overall response rate (ORR) in the FL cohort (n = 86) was 94%, including a 79% complete response (CR) rate. In the MZL group (n = 24), the ORR was 83% with a 63% CR rate.

“This higher response rate translated to good durability,” Neelapu said. “The estimated median duration of response for the follicular lymphoma cohort was approximately 39 months and it was not reached for the marginal zone lymphoma cohort.”

The FDA approved axi-cel for the treatment of adult patients with relapsed/refractory follicular lymphoma following 2 or more lines of systemic therapy in March 2021 based on previous data from ZUMA-5. The chimeric antigen receptor (CAR) T-cell product elicited a response in 91% of patients with relapsed/refractory follicular lymphoma (n = 81) including a CR of 60%. Notably, 74% of patients had a continued remission at 18 months.2

ZUMA-5 is a multicenter, single-arm study of patients with relapsed/refractory iNHL who previously received 2 or more lines of systemic therapy, including treatment with an anti-CD20 monoclonal antibody and an alkylating agent. The primary end point was ORR per central review. Key secondary end points included duration of response, progression-free survival (PFS), OS, and safety.

To be eligible for enrollment, patients had to have an ECOG performance status of 0 or 1. Participants underwent leukapheresis and received conditioning chemotherapy followed by an infusion of axi-cel at 2 × 10⁶ CAR T cells/kg.In the primary analysis (N = 104) presented at ASH in 2020 after a median follow-up of 17.5 months, the ORR was 92% with a CR rate of 76%.³

In these updated findings, the median PFS was 39.6 months (95% CI, 25.7 to not estimable [NE]) in the follicular lymphoma group with a 24-month PFS of 63.4% (95% CI, 51.6%-73.0%). In the MZL group, the median PFS was 17.3 months (95% CI, 9.2-NE) and the 24-month PFS was 47.4% (95% CI, 23.1%-68.4%).

Investigators evaluated efficacy outcomes in 78 patients with follicular lymphoma by progression of disease within 24 months (POD24; starting from initiation of anti-CD20–containing chemotherapy) status. In patients with POD24 (n = 49), the median duration of response (DOR) was 38.6 months (95% CI, 14.5-NE) with a 24-month DOR of 61.1% (95% CI, 44.3%-74.3%). In those without POD24 (n = 29), the median DOR was not reached (95% CI, 24.7-NE) and the 24-month DOR was 72.4% (95% CI, 50.2%-85.9%).The median PFS was 39.6 months (95% CI, 13.1-NE) and the median OS was not reached (95% CI, 39.6-NE) with POD24 vs not reached (95% CI, 25.7 months-NE) and not reached (95% CI, NE-NE), respectively, without POD24.The 24-month PFS was 57.3 months (95% CI, 41.2-70.4) and the 24-month OS was 77.6% (95% CI, 63.1%-86.9%) with POD24 vs 73.0% (95% CI, 51.1%-86.2%) and 85.9% (95% CI, 66.7%-94.5%), respectively, without POD24.

“The efficacy outcomes in patients with POD24 were quite consistent with all efficacy-eligible patients,” Neelapu said. He added that POD24 results were consistent across key prognostic subgroups, including patients older than 65 years; those who had high tumor burden by GELF criteria; those who were refractory to last previous therapy; and those who had prior stem cell transplantation or prior exposure to lenalidomide, a BTK inhibitor, or a PI3 kinase inhibitor.

Neelapu said the updated safety results were consistent with previous findings. The most common grade 3 or higher adverse events were neutropenia (33%), decreased neutrophil count (28%), and anemia (25%).

There were only 2 incidents of cytokine release syndrome (CRS) observed after data cutoff for the primary analysis; both were in the MZL group and both were grade 1/2. Similarly, there were only 2 incidents of neurologic events observed after the primary analysis; again, both were in the MZL group and both were grade 1/2.

“As of the date of the data cutoff, most CRS cases and neurological events have resolved,” Neelapu said.

Six patients died of infections following data cutoff for the primary analysis. Three were related to axi-cel or conditioning therapy.

References

1. Neelapu SS, Chavez JC, Sehgal AR, et al. Long-term 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). Presented at: 63rd ASH Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 0093.
2. US FDA approves Yescarta for relapsed or refractory follicular lymphoma after two or more lines of systemic therapy. News release. Kite. December 11, 2021. Accessed March 5, 2021. http://bit.ly/3kOyKnb
3. Jacobson C, Chavez JC, Sehgal AR, et al. Primary 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). December 5-8, 2020; Virtual. Abstract #700.