Approval of axi-cel in second-line for R/R LBCL & label update

Axicabtagene ciloleucel (axi-cel) was approved by the FDA in October 2017 for patients with large B-cell lymphoma (LBCL) after two or more lines of systemic therapy based on the results of the ZUMA-1 trial (NCT02348216).1 While this drug has significantly improved the outcomes of relapsed/refractory (R/R) patients, the durability of response to axi-cel is limited and the risk of relapse remains high. To investigate whether introducing axi-cel earlier in the treatment algorithm led to improved outcomes, three Phase III clinical trials were launched to compare three different CAR-T therapies to chemoimmunotherapy followed by autologous hematopoietic stem cell transplantation (autoHSCT) in patients with R/R LBCL in the second-line setting.2–4

In this video, Evandro Bezerra, MD, Mayo Clinic, Rochester, MN, talks on the recent approval of axi-cel for LBCL in the second line, and discusses the recent label update of axi-cel.

ZUMA-7 (NCT03391466), TRANSFORM (NCT03575351), and BELINDA (NCT03570892) compared axi-cel, lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel) respectively to standard of care (SOC). While ZUMA-7 and TRANSFORM reported statistically significant improvements for patients treated with CAR-T therapy, BELINDA did not show any benefit for patients treated with tisa-cel.2–4 More specifically, in ZUMA-7, the 18-month event-free survival (EFS) rate in the axi-cel arm was 41.5% (95% CI: 34.2, 48.6) compared to 17% (95% CI: 11.8, 23.0) in the SOC arm, and the median EFS was 8.3 months (95% CI: 4.5, 15.8) in the CAR-T group and 2.0 months (95% CI: 1.6, 2.8) in the SOC group. Of interest, 90% (Grade ≥3, 9%) of patients experienced cytokine release syndrome (CRS) and 78% (Grade ≥3, 25%) experienced neurological events. Based on these results, the FDA approved axi-cel in second line for LBCL on April 1st, 2022. This approval is expected to greatly impact the outcomes of patients with primary refractory disease.5

Additionally, the FDA also approved an update to the prescribing information for axi-cel in early 2022. This update allowed for the use of prophylactic corticosteroids across all approved indications to better manage toxicities. This update was based on the findings of the ZUMA-1 study (NCT02348216) which assessed the impact of prophylactic corticosteroids on the incidence and severity of CRS and neurological events in a safety management cohort (Cohort 6). The study reported that none of the patients in this cohort experienced grade 3 or above CRS compared to 13% in the pivotal Cohorts 1 and 2 , and 13% of patients in Cohort 6 experienced grade 3 or above neurologic events compared to 31% in Cohorts 1 and 2.6 Data presented at ASH 2021 suggested that these toxicity management strategies do not impact the activity of axi-cel.7

CAR-T therapies are being developed and approved in a growing number of indications. It is therefore essential to find new strategies to mitigate the toxicity associated with these products. A number of ongoing studies are testing various approaches to reduce the incidence and severity of adverse events caused by CAR-T therapy. Additionally, multiple studies are also exploring strategies to improve the efficacy and durability of axi-cel and other CAR-Ts in various indications. Importantly, ZUMA-12 (NCT03761056), the first prospective Phase II trial to evaluate CAR-Ts as first-line therapy in patients with high-risk LBCL is currently underway and has reported remarkable results so far.8


  1. US Food and Drug Administration. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. Available from: (Last accessed 31/05/22).
  2. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. The New England Journal of Medicine. 2022 February 17; 386:640-654.
  3. Kamdar M, Solomon SR, Arnason JE, et al. Lisocabtagene Maraleucel (liso-cel), a CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy, Versus Standard of Care (SOC) with Salvage Chemotherapy (CT) Followed By Autologous Stem Cell Transplantation (ASCT) As Second-Line (2L) Treatment in Patients (Pts) with Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL): Results from the Randomized Phase 3 Transform Study. Blood. 2021 November 23; 138(1), 91.
  4. Bishop MR, Dickinson M, Purtill D, et al. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. The New England Journal of Medicine. 2022 February 17. 386:629-639
  5. US Food and Drug Administration. FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. Available from,FDA%20approves%20axicabtagene%20ciloleucel%20for%20second%2Dline,of%20large%20B%2Dcell%20lymphoma&text=On%20April%201%2C%202022%2C%20the,%2C%20Kite%20Pharma%2C%20Inc (Last accessed 31/05/22).
  6. Business Wire. U.S. FDA Approves New Label Update for CAR T-Cell Therapy Yescarta® Showing Prophylactic Steriod Use Improves Management of Cytokine Release Syndrome. Available from (Last accessed 31/05/22).
  7. Oluwole OO, Forcade E, Muñoz J, et al. Prophylactic Corticosteroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients (Pts) with Relapsed/Refractory Large B-Cell Lymphoma (R/R LBCL): One-Year Follow-up of ZUMA-1 Cohort 6 (C6). Blood. 2021 December 24; 138 (1), 2832
  8. Neelapu SS, Dickinson M, Muñoz J, et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nature Medicine. 2022 March 21; 28, 735–742

Written by Elitsa Kamberska

Edited by Thomas Southgate