Car rates

First concrete results with Brexu-Cel in MCL demonstrate feasibility and positive efficacy

A real-world outcome evaluation with brexucabtagene autoleucel (brexu-cel; Tecartus) in patients with mantle cell lymphoma (MCL) indicated that CAR T-cell therapy was both feasible and effective, despite its use in a population with a wide range of baseline characteristics and high-risk characteristics.1

The median time to initial response was 30 days (range: 16-104) after treatment with brexu-cel, with a 30-day overall response rate (ORR) of 88% in an evaluable population of 92 patients , including a complete response (CR) of 66% and a partial response rate (PR) of 22%.

Notably, the best ORR in the real-world study was 89%, which was comparable to the Phase 2 ZUMA-2 trial (NCT02601313), which reported a rate of 93%.2 In addition, 9% of patients had progressive disease and 1% had stable disease. One of the 2 patients whose disease was stable at day 30 achieved CR after a median of 64 days.

When responses were assessed by patient subgroup, investigators reported an ORR of 95% and a CR rate of 87% in those with blastoid/pleomorphic morphology (n=39); 87% and 71%, respectively, for those with a TP53 deletion or mutation (n = 31); 90% and 78% in those with a Ki67 percentage score of 50% or greater (n=50); 82% and 64% in those with a high score on the simplified international prognostic index for mantle cell lymphoma (n = 11); and 86% and 57% for those with central nervous system (CNS) involvement (n=7). Additionally, Burton’s tyrosine kinase (BTK) inhibitor naïve patients (n=17) had an ORR of 94% and a CR rate of 88%, and those who were not eligible for ZUMA-2 trial (n=74) had rates of 91%% and 80%, respectively.

In terms of additional study results, researchers reported that the median duration of response (DOR) was not reached after a median follow-up of 6.7 months (range, 0.5-13.6) . The 6-month DOR rate was 70% (95% CI, 57% to 80%), which was comparable to ZUMA-2 results. In addition, median progression-free survival (PFS) and overall survival (OS) were not achieved. The PFS rates at 6 and 12 months were 66% (95% CI, 54%-75%) and 51% (95% CI, 37%-64%), respectively. Additionally, the OS rates at 6 and 12 months were 81% (95% CI, 70% to 88%) and 72% (95% CI, 57% to 82%), respectively.

Eligibility criteria for the ZUMA-2 trial included having between 1 and 5 prior lines of therapy, including an anti-CD20 agent, anthracycline or bendamustine, and ibrutinib (Imbruvica) or acalabrutinib (Calquence); an ECOG performance status of 2 or less; adequate blood count, liver function and kidney function; and no significant comorbidity. Bridging therapies included corticosteroids, ibrutinib, and acalabrutinib.2

A total of 14 centers participated in the study, which included patients who underwent leukapheresis before June 2021 to make brexu-cel. Investigators collected data related to clinical characteristics, transition therapy, adverse events (AEs) after brexu-cel treatment, and post-infusion outcomes.

One hundred and seven patients underwent leukapheresis, of which 12 did not receive infusion due to manufacturing defect (n=6), organ dysfunction (n=1), or death (n = 5). Ninety-five patients received a brexu-cel infusion.

Patients included in the analysis had a median age of 67 years (range, 34-89) and most were male (80%). Additionally, 57% of patients had a Ki-67 percentage score of 50% or greater and 41% had blastoid/pleomorphic morphology (41%). Forty-four percent of patients had a TP53 mutation or deletion and 29% had a complex karyotype.

Treatment-related reasons for ZUMA-2 ineligibility included receiving more than 5 lines of treatment (13%), not having previously received a BTK inhibitor (18%), or not having received CD20 agent, anthracycline or bendamustine (14%). Other reasons for ineligibility included absolute neutrophil count less than 1000/µL (8%), absolute lymphocyte count less than 100/µL (1%), platelet count less than 75,000/µL ( 5%), a creatinine level greater than 1.5 mg/dL (8%), or a creatinine clearance less than 60 mL/minute (20%). In particular, 78% of the patients included in the analysis would not have fulfilled the inclusion criteria for the ZUMA-2 trial.

In total, 67% of patients benefited from relay treatment, with a median delay between leukapheresis and lymphodepleting chemotherapy of 23 days. The median time between lymphodepleting chemotherapy and CAR T cell infusion was 5 days.

Of those treated, 91% developed cytokine release syndrome (CRS) and 60% developed immune effector cell-associated neurotoxicity syndrome (ICANS). Eight percent of all CRS events and 35% of ICANS events were severity 3 or 4. The incidence of CRS and ICANS was comparable to events seen in the ZUMA-2 trial. The median time to onset of events was 4 and 6 days, respectively, and a median duration of 5 and 6 days. Events were most often managed with tocilizumab (Actemra; 79%), steroids (69%), which appeared to be more frequent than in ZUMA-2. Twenty-one percent of patients were admitted to intensive care for a median of 3 days, with 11% requiring vasopressors, 4% mechanical ventilation, and 3% dialysis (3%).

These findings were presented at the Tandem Meeting 2022.

References

  1. Munoz J, Wang Y, Jain P, et al. Brexucabtagene’s Autoleucel for relapsed/refractory mantle cell lymphoma: real-world experience from the US lymphoma CAR T Consortium. Presented at: 2022 Transplantation & Cellular Therapy Meetings; Salt Lake City, Utah; April 23-26, 2022. Abstract 265.
  2. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-Cell therapy in relapsed or refractory mantle cell lymphoma. N English J med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347