FDA Approval Sought for Axicabtagene Ciloleucel in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma


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A supplemental biologics license application has been filed with the FDA for axicabtagene ciloleucel for the treatment of relapsed or refractory follicular lymphoma and marginal zone lymphoma following 2 or more previous lines of systemic therapy.

Ken Takeshita, MD

Ken Takeshita, MD

A supplemental biologics license application (BLA) has been filed with the FDA for axicabtagene ciloleucel (axi-cel; Yescarta) for the treatment of relapsed or refractory follicular lymphoma and marginal zone lymphoma (MZL) following 2 or more previous lines of systemic therapy, according to an announcement from Kite Pharma, the developer of the CAR T-cell product.1

The sBLA was based on data from the primary analysis of the phase 2 ZUMA-5 trial (NCT03105336), which has been submitted for presentation at an upcoming medical meeting.

“People living with indolent non-Hodgkin lymphoma (NHL) often experience a disease that starts out slowly but becomes more aggressive over time with each subsequent relapse,” Ken Takeshita, MD, Global Head of Clinical Development at Kite, stated in a press release. “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 [axicabtagene ciloleucel] to patients with indolent NHL as soon as possible.”

Data from an interim analysis of ZUMA-5 were presented during the 2020 ASCO Virtual Scientific Program and showed that the CD19-targeted therapy showed significant and durable benefit with high rates of responses in patients with follicular lymphoma and MZL.2

Of the 96 efficacy-evaluable patients, the objective response rate (ORR) with axi-cel was 93% (95% CI, 86-97) with a complete response (CR) rate of 80% (95% CI, 71-88). The median time to the first response with the product was 1 month. When broken down by subtype, those with FL (n = 80) experienced an ORR of 95% with an 81% CR rate, while those with MZL (n = 16) reported an ORR of 81% with a 75% CR rate.

At a median follow-up of 15.3 months, the estimated duration of response (DOR) in all participants was 20.8 months, with more than half, or 68%, of those with FL experiencing an ongoing response to the CAR T-cell therapy at the time of data cutoff. Although the median progression-free survival (PFS) with axi-cel had not yet been reached, the 12-month OS rate was 94.3% (95% CI, 86.8-97.6) for all participants.

To be eligible for the single-arm, multicenter, open-label ZUMA-5 trial, adults had to have relapsed or refractory follicular lymphoma (grades 1-3a) or MZL (nodal or extranodal) following 2 or more lines of previous treatment including an anti-CD20 monoclonal antibody with an alkylating agent and they needed to have an ECOG performance status of 0 or 1.

In the trial, participants were leukapheresed and were given conditioning chemotherapy followed by an infusion of the CAR T-cell product at 2 × 106 CAR T-cells/kg. The primary end point of the trial was ORR per central review, while key secondary end points included DOR, PFS, overall survival, safety, and blood levels of cytokines and CAR T cells.

At the time of data cutoff, December 16, 2019, a total of 140 patients underwent treatment with the CD19-targeted CAR T-cell product; 124 of these patients had follicular lymphoma and 16 had MZL. The median age of participants was 63 years and 49% were male. Moreover, just over half, or 52%, had stage IV disease, 51% had a FLIPI score of 3 or higher, and 49% had high tumor bulk. Participants had received a median of 3 previous lines of treatment and 66% experienced disease progression less than 2 years after treatment with anti-CD20 monoclonal antibody–containing treatment was received. Seventy-three percent of patients were refractory to their last treatment.

With regard to safety, 85% of patients (n = 119) experienced adverse effects (AEs) that were grade 3 or higher. The most commonly reported AEs included neutropenia (34%) and anemia (22%). Moreover, grade 3 or higher cytokine release syndrome (CRS) was observed in 8% of patients, while neurologic events were reported in 17% of patients. Only 2 grade 5 toxicities occurred, and they included multisystem organ failure in the context of CRS, which was linked with the study drug, and aortic dissection, which was not related to study treatment.

Additionally, the median time to peak of anti-CD19 CAR T-cell levels following infusion with axi-cel was 8 days. Furthermore, the anti-CD19 CAR T cells were identifiable at 18 months in the majority of participants who had samples eligible for assessment (87%; n = 13/15).

In patients with follicular lymphoma, peak CAR T-cell expansion was linked with grade 3 or higher CRS (P = .0088) as well as neurologic events (P = .0076). Moreover, peak serum analyses spanning several immune programs were linked with grade 3 or higher CRS, neurologic events, or both in this patient subgroup.

“The ZUMA-5 trial is designed as a pivotal study for axi-cel. [An FDA approval] would lead to an expanded indication for axi-cel among our patients with lymphoma,” said Caron Jacobson, MD, medical director of the Immune Effector Cell Therapy Program and physician at Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School, told OncLive in a recent interview. “If the durability proves to be robust and the safety profile continues to be reproducible, we could start thinking about designing clinical trials with axi-cel or other CAR T-cell therapies in earlier lines of therapy.”

In October 2017, the FDA approved axi-cel for use in adult patients with certain types of large B-cell lymphoma who have not responded to or who have relapsed following at least 2 other kinds of therapies; this was the first CAR T-cell product to receive regulatory approval for this patient population. If this new indication is approved, it will also be the first CAR T-cell product for patients with relapsed or refractory follicular lymphoma and MZL, according to Kite.


  1. Kite submits supplemental biologics license application to US Food and Drug Administration for Yescarta in relapsed or refractory indolent non-Hodgkin lymphomas. News release. Kite Pharma. September 4, 2020. Accessed September 4, 2020. https://bwnews.pr/3jPkjOa.
  2. 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
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