Axi-Cel Provides Durable Responses in Higher-Risk Follicular Lymphoma and MZL, Regardless of POD24 Status

Axicabtagene ciloleucel (axi-cel; Yescarta) demonstrated significant clinical activity with durable responses in patients with relapsed/refractory indolent non-Hodgkin lymphoma (iNHL) who experienced disease progression within 24 months from initiation of the first anti-CD20–containing chemotherapy (POD24), which is a high-risk clinical feature, according to findings from an updated analysis of the phase 2 ZUMA-5 trial (NCT03105336) that were presented during the European Hematology Association 2021 Virtual Congress.

The overall response rates (ORRs) were similar among the efficacy-evaluable patient populations with (n = 61) and without (n = 37) POD24 at 92% in both groups. In the POD24 cohort, this comprised a 74% complete response (CR) rate and an 18% partial response (PR) rate. In those without POD24, these rates were 86% and 5%, respectively.

The median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were all not reached (NR) in patients regardless of POD24 status. The 18-month DOR, PFS, and OS rates in those with POD24 were 59.6%, 55.3%, and 84.5%; in patients without POD24, these rates were 77.6%, 84.1%, and 94.2%, respectively.

In patients with follicular lymphoma, the ORR was 94% (n = 46) in patients with POD24 (n = 49) compared with 97% (n = 28) in patients without POD24 (n = 29). The CR rates were 78% (n = 38) vs 90% (n = 26), respectively, and the PR rates were 16% (n = 8) vs 7% (n = 2), respectively.

In patients with marginal zone lymphoma (MZL), the ORR was 83% (n = 10) in patients with POD24 (n = 12) compared with 75% (n = 6) in patients without POD24 (n = 8). The CR rates were 58% (n = 7) vs 75% (n = 6), respectively, and the PR rates were 25% (n = 3) and 0%, respectively.

Additionally, with median follow-ups of 17.1 months and 17.5 months, respectively, responses were ongoing in 52% of evaluable patients with POD24 compared with 70% of those without POD24.

“These results indicate that axi-cel may be a promising therapy for patients with POD24, a group in need of improved treatment options,” said lead study author Caron A. Jacobson, MD, MMSc, medical director of the Immune Effector Cell Therapy Program and a senior physician at Dana-Farber Cancer Center, and an assistant professor of medicine at Harvard Medical School, in a presentation of the data.

POD24 is associated with poor survival among patients with iNHL and data suggest that patients with follicular lymphoma can have up to a 50% lower 5-year OS rate compared with patients without early progression. Moreover, patients with POD24 account for approximately 20% of all patients with follicular lymphoma.

Axi-cel, an autologous anti-CD19–directed CAR T-cell therapy is FDA approved for use in patients with relapsed/refractory follicular lymphoma following 2 or more prior lines of systemic therapy, as well as for patients with relapsed/refractory large B-cell lymphoma following 2 or more lines of prior systemic therapy.

The FDA approval in follicular lymphoma was based on findings from the ZUMA-5 trial, which reported a response rate of 91% with a CR rate of 60% in patients with relapsed/refractory follicular lymphoma. Moreover, the results of the primary analysis reported similar ORRs in patients with and without POD24 after 17.5 months of follow-up.

In ZUMA-5, patients with relapsed/refractory grade 1 to 3a follicular lymphoma or nodal or extranodal MZL (n = 148) underwent leukapheresis followed by conditioning chemotherapy with fludarabine and cyclophosphamide. Then, patients received a single infusion of axi-cel at 2 x 106 CAR+ cells/kg on day 0.

The POD24 analysis included 129 axi-cel–treated patients with follicular lymphoma or MZL who had available data on progression after an anti-CD20 monoclonal antibody and an alkylating agent.

Patient characteristics were similar between those with and without POD24. Most patients had follicular lymphoma (83.5%), were male (59.5%), and had stage III or IV disease (88.5%). Patients with POD24 were a median age of 60 years (range, 34-78) and patients without POD24 were a median age of 62 years (range, 42-79).

Less than half of patients (43.5%) had a Follicular Lymphoma International Prognostic Index score of 3 or greater, and just under half of patients (47.5%) had high tumor bulk per Groupe d'Etude des Lymphomes Folliculaires criteria.

The majority of patients (67.5%) had received 3 or more prior therapies, which included PI3K inhibitors (with POD24, 27%; without POD24, 35%) and lenalidomide (Revlimid; with POD24, 31%; without POD24, 40%). Twenty percent of patients with POD24 had undergone autologous stem cell transplant compared with 23% of patients without POD24. Finally, 77% vs 63% of patients had refractory disease, respectively.

In the follicular lymphoma cohort, median tumor burden was similar in those with POD24 (2303 mm2) vs without (2839 mm2). In MZL, tumor burden was higher in patients with POD24 (2028 mm2) vs those without (954 mm2).

Additional efficacy data reported that the median DOR in the follicular lymphoma cohort was NR in either group with or without POD24 (with POD24; 95% CI, 14.5-not evaluable [NE]; without POD24; 95% CI, 20.8-NE). The 18-month DOR rate was 63.9% (95% CI, 47.2%-76.6%) in patients with POD24 vs 78.2% (95% CI, 53.3%-90.8%) in patients without POD24.

In the MZL cohort, the median DOR was 11.1 months (95% CI, 1.9-NE) in patients with POD24 vs NR (95% CI, 10.6-NE) in patients without POD24. The 18-month DOR rates were NE (95% CI, NE-NE) vs 75.0% (95% CI, 12.8%-96.1%), respectively.

The median PFS in the follicular lymphoma cohort was also NR in either group with or without POD24 (with POD24; 95% CI, 13.1-NE]; without POD24; 95% CI, 23.5-NE). The 18-month PFS rates were 59.8% (95% CI, 43.7%-72.6%) vs 85.3% (95% CI, 65.4%-94.2%), respectively.

In the MZL cohort, the median PFS was 9.2 months (95% CI, 2.8-NE) in patients with POD24 vs NR (95% CI, 11.8-NE) in patients without POD24. The 18-month PFS rates were 30.7% (95% CI, 5.1%-62.6%) vs 75.0% (95% CI, 12.8%-96.1%), respectively.

Finally, the median OS in the follicular lymphoma cohort was NR in either group with (95% CI, 31.6-NE) or without (95% CI, NE-NE) POD24. The 18-month OS rates were 85.7% (95% CI, 72.4%-92.9%) vs 93.1% (95% CI, 75.1%-98.2%), respectively.

In the MZL cohort, the median OS was NR in either group with (95% CI, 13.7-NE) or without POD24 (95% CI, 18.7-NE). The 18-month OS rates were 76.4% (95% CI, 30.9%-94.0%) vs 100% (NE-NE), respectively.

Additionally, the expansion of CAR T cells following infusion was similar in patients with and without POD24. The median peak CAR T-cell levels and AUC0-28 was also similar between groups.

Notably, pretreatment analyte levels of CCL17 and CCL22, which were previously associated with relapse, appeared to be higher in patients with POD24 compared with those without, Jacobson said. Axi-cel therapy attributes, pharmacokinetics, and pharmacodynamics were also generally similar across evaluable patients.

In the broader ZUMA-5 patient population, 14 patients had available data at relapse after axi-cel. Of these patients, 100% had detectable CD19 that was confirmed in all evaluable biopsies irrespective of POD24 status.

Regarding safety, any-grade adverse effects (AEs) were observed in 99% of patients with POD24 (n = 81) vs 100% of patients without POD24 (n = 48). Grade 3 or greater AEs were reported in 84% vs 88% of patients, respectively, including cytopenias (69% vs 65%, respectively) and infections (15% vs 21%, respectively). Serious AEs were observed in 46% of patients with POD24 vs 54% of patients without POD24.

Grade 5 events occurred in 3 patients with POD24, including 1 event of cytokine release syndrome (CRS), and no grade 5 events occurred in patients without POD24.

Any-grade CRS was observed in 81% of patients with POD24 vs 88% of patients without POD24; grade 3 or higher CRS was noted in 9% vs 2% of patients, respectively. The median time to CRS onset was 4 days in both groups. The median duration of CRS was 7 days among patients with POD24 and 5 days among those without POD24.

Neurologic toxicity was observed in 57% of patients with POD24 vs 65% of patients without POD24; grade 3 or higher neurologic events were reported in 17% of patients in both cohorts. The median time to onset of neurologic toxicity was 8 days vs 7 days, respectively, and the median duration of the events were 11 days vs 13 days, respectively.

Notably, peak levels of key biomarkers associated with axi-cel toxicity generally similar across all patients treated.

“POD24 was associated with a lower complete response rate, earlier risk of relapse, and decreased progression-free survival in marginal zone lymphoma, but this effect was less pronounced in patients with follicular lymphoma,” concluded Jacobson.

Reference

Jacobson CA, Chavez JC, Sehgal AR, et al. Outcomes in ZUMA-5 with axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory indolent non-Hodgkin lymphoma who had the high-risk feature of progression within 24 months from initiation of first anti-CD20–containing chemoimmunotherapy (POD24). Presented: European Hematology Association 2021 Virtual Congress; June 9-17, 2021; virtual. Abstract S213.