FDA to Review sBLA for Axi-Cel in R/R Follicular Lymphoma and Marginal Zone Lymphoma

September 5, 2020

The FDA has accepted a supplemental Biologics License Application for axicabtagene ciloleucel for the treatment of patients with relapsed or refractory follicular lymphoma or marginal zone lymphoma after 2 or more prior lines of systemic therapy.

The FDA has accepted a supplemental Biologics License Application (sBLA) for axicabtagene ciloleucel (axi-cel; Yescarta) for the treatment of patients with relapsed or refractory follicular lymphoma (FL) or marginal zone lymphoma (MZL) after 2 or more prior lines of systemic therapy.1

This would be the first potential CAR T-cell therapy for patients with relapsed/refractory FL and MZL.

Data supporting the sBLA come from the primary analysis of the phase 2 ZUMA-5 trial.

“People living with indolent NHL [non-Hodgkin lymphoma] often experience a disease that starts out slowly but becomes more aggressive over time with each subsequent relapse,” Ken Takeshita, MD, the global head of clinical development at Kite, said in a statement. “The efficacy observed in ZUMA-5 may provide a potentially transformative treatment option for higher-risk patients with certain types of indolent NHL. We look forward to working closely with the FDA to progress this application with the goal of bringing Yescarta to patients with indolent NHL as soon as possible.”

Findings from the interim analysis of the ZUMA-5 trial were presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program.2

The ZUMA-5 trial, which is ongoing, is a multicenter, single-arm phase 2 study exploring the safety and efficacy of axi-cel in patients with relapsed/refractory indolent NHL after at least 2 prior lines of therapy (NCT03105336). A total of 160 patients are planned for enrollment, consisting of about 125 with FL and 35 with MZL.

Eligible patients had grade 1 to 3a R/R FL or nodal or extranodal MZL as well as at least 2 prior lines of therapy including an anti-CD20 monoclonal antibody combined with an alkylating agent.

All patients received a conditioning regimen of intravenous fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 on days 5 through 3 prior to initiation of axi-cel at 2 x 106 CAR cells/kg as a single infusion.

The primary end points of the study are objective response rate (ORR) by independent radiologic review committee (IRRC) per Lugano classification, and key secondary end points included complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), adverse events (AEs), and CAR T cells and cytokine levels.

Of 148 patients enrolled as of the interim analysis, 140 received axi-cel including 124 with FL and 16 with MZL. Ninety-six patients were included in the efficacy analysis, which included the first 80 patients with FL with at least 9 months of follow-up and the 16 patients with MZL with at least 1 month of follow up. All 140 treated patients were included in the safety analysis. The median follow-up for the efficacy analysis was 15.3 months (range, 1.9-28.8) and 12.8 months (range, 1.9-28.8) for the safety analysis.

At baseline, the patients with FL had a median age of 62 years (range, 34-79), 54% were male, 41% had an ECOG performance status of 1, 46% had stage IV disease, 48% had a FLIPI score of 3 or higher, and 50% had high tumor bulk. Patients had received a median of 3 prior therapies (range, 2-9), including prior PI3K inhibition in 33% and autologous stem cell transplant in 24%. Seventy-four percent had refractory disease and 56% had progression of disease less than 2 years from their first anti-CD20 monoclonal antibody–containing regimen.

In the MZL population, the median age was 67 years (range, 52-77), 25% were male, 38% had an ECOG performance status of 1, 81% had stage IV disease, 69% had a FLIPI score of 3 or higher, and 44% had high tumor bulk. The median number of prior therapies was 3 (range, 2-8) with 38% having received a PI3K inhibitor and 19% having undergone autologous stem cell transplant. Additionally, 69% were refractory and 44% had progression of disease less than 2 years from their first anti-CD20 monoclonal antibody–containing regimen.

The overall ORR by IRRC was 93% (95% CI, 86%-97%) and CRs were observed in 80% (95% CI, 71%-88%). In the FL population, the ORR was 95% with CRs in 81%, and in the MZL population the ORR was 81% consisting of CRs in 75%. The median time to first response was 1 month (range, 0.8-3.1).

By subgroup analysis, ORRs ranged from 85% to 96%. The lowest ORR was observed in patients who relapsed less than 6 months from their first anti-CD20 monoclonal antibody–containing regimen (85%). An ORR of 96% was found in patients who received 3 prior lines of therapy, had high-risk disease, and in patients with high tumor bulk.

Median DOR was 20.8 months overall and in patients with FL. Among patients with MZL, the median DOR was 10.6 months. At 15.3 months of follow-up, 68% of patients with FL had an ongoing response.

The median PFS was 23.5 months in the FL group and 11.8 months in the MZL group. Median OS was not reached in each arm, but the 1-year OS rate was 93.4% in the FL population and 100% in the MZL population.

The most common treatment-emergent adverse events (TEAEs) were pyrexia in 84% of all patients, hypotension in 49%, fatigue in 44%, headache in 44%, nausea in 39%, neutropenia in 36%, and anemia in 35%. Grade 3 or higher TEAEs were reported in 85% of all patients, with the most common being neutropenia (34%), decreased neutrophil count (28%), and anemia (22%). Grade 5 AEs were reported in 2 patients with FL, including 1 case of multisystem organ failure due to cytokine release system (CRS) related to treatment and a case of aortic dissection that was unrelated to treatment.

CRS of any grade was observed in 77% of patients with FL and all of the patients with MZL; CRS of grade 3 or higher was reported in 7% and 13% of patients with FL and MZL, respectively. The most common symptoms of CRS were pyrexia and hypotension. The median time to CRS onset was 4 days and the median duration was 6 days. As of the data cutoff, no patients had ongoing CRS.

Neurologic events of any grade were reported in 55% of patients with FL and 81% of those with MZL; cases were of grade 3 or higher in 15% and 38% of the FL and MZL population, respectively. The most common symptoms were tremor and confusional state. The median time to onset was 7 days and the median duration was 13 or 14 days. Ninety-five percent of cases resolved as of data cutoff.

Previously, the FDA granted axi-cel with a breakthrough therapy designation for these indications.

Axi-cel was the first CAR T-cell therapy to approved by the FDA and is currently indicated for the treatment of adult patients with relapsed/refractory large B-cell lymphoma after at least 2 lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, and high grade B-cell lymphoma and DLBCL arising from FL.

References

Kite Submits Supplemental Biologics License Application to U.S. Food and Drug Administration for Yescarta in Relapsed or Refractory Indolent Non-Hodgkin Lymphomas. News release. Kite. September 4, 2020. Accessed September 4, 2020. https://bwnews.pr/2QVoHi1

Jacobson CA, Chavez JC, Sehgal AR, et al. Interim analysis of ZUMA-5: A phase II study of axicabtagene ciloleucel (axi-cel) in patients (pts) with relapsed/refractory indolent non-Hodgkin lymphoma (R/R iNHL). J Clin Oncol. 2020;38(suppl 15):8008. doi:10.1200/JCO.2020.38.15_suppl.8008