Brexucabtagene Autoleucel Displays Continued Durability, Safety in Relapsed/Refractory MCL

Brexucabtagene autoleucel (Tecartus; formerly KTE-X19) displayed significant and durable responses and a reduction in adverse effects (AEs) in patients with relapsed/refractory mantle cell lymphoma (MCL), according to extended follow-up data from the phase 2 ZUMA-2 trial that were presented virtually during the 47th Annual Meeting of the EBMT.¹

At a median follow-up of 17.5 months (range, 12.3-37.6), the objective response rate (ORR) was 92% (95% CI, 82%-97%), the complete response (CR) rate was 67% (n = 40; 95% CI, 53%-78%), and the partial response rate was 25% (n = 15). The stable disease and progressive disease rates were both 3% (n = 2 each).

Twenty-nine of 60 evaluable patients (48%) remain in ongoing responses, and 28 of 40 patients who achieved a CR (70%) remain in response. The first 28 patients treated had a median follow-up of 32.3 months (range, 30.6-37.6); 39% of patients remain in remission without additional treatment.

In all enrolled patients (n = 74), the ORR was 84%, and the CR rate was 59%.

“The ZUMA-2 study continues to show substantial and durable clinical benefit and a manageable safety profile with [brexucabtagene autoleucel] therapy in patients with relapsed/refractory MCL with extended follow-up,” said Michael L. Wang, MD, lead study author and professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, in a presentation of the data.

Poor outcomes are associated with patients with relapsed/refractory MCL who progress on BTK inhibitors. These patients typically derive an ORR of 25% to 42% and an overall survival (OS) of 6 to 10 months with salvage therapy.

In July 2020, the FDA approved brexucabtagene autoleucel, an autologous CD19-directed CAR T-cell therapy, for the treatment of patients with relapsed/refractory MCL based on findings from the ZUMA-2 trial, in which a single infusion of the CAR T-cell product elicited an 87% ORR in patients with relapsed/refractory MCL and a 62% CR rate.²

The pivotal ZUMA-2 trial evaluated brexucabtagene autoleucel in patients with relapsed/refractory MCL who received 1 to 5 prior lines of therapy, including a BTK inhibitor. In the primary efficacy analysis (n = 60), the ORR was 93% and the CR rate was 67% at a median follow-up of 12.3 months.

In the study, patients underwent leukapheresis followed by optional bridging therapy, conditioning chemotherapy, CAR T-cell infusion, and follow-up.

Bridging therapy consisted of 20 mg to 40 mg of dexamethasone daily for 1 to 4 days, 560 mg of ibrutinib (Imbruvica) daily or 100 mg of acalabrutinib (Calquence) twice daily. Conditioning chemotherapy comprised 30 mg/m2 of fludarabine and 500 mg/m2 of cyclophosphamide on days -5, -4, and -3. Brexucabtagene autoleucel was administered as a single infusion at a dose of 2 x 106 cells/kg on day 0. During follow-up, the first tumor assessment was made on day 28.

ORR served as the primary end point. Secondary end points included duration of response (DOR), progression-free survival (PFS), OS, AEs, and levels of CAR T cells in the blood and cytokines in serum.

Additional results showed that the median DOR, PFS, and OS had not been reached at the median follow-up. Among all evaluable patients (n = 60), the 15-month DOR, PFS, and OS rates were 59% (95% CI, 43%-72%), 59% (95% CI, 45%-71%), and 76% (95% CI, 63%-85%), respectively.

Moreover, the ongoing ORR was comparable across adverse prognostic subgroups, including s-

Mantle Cell Lymphoma International Prognostic Index score, Ki-67 proliferation index, morphological characteristics, and TP53 mutation status.

No new safety signals were reported with additional follow-up, and no new CRS or grade 5 events occurred since the prior report.

Among all treated patients (n = 68), the AEs that were present for 3 months or greater post-infusion included anemia (any-grade, 32%; grade ≥3, 13%), neutropenia (any-grade, 29%; grade ≥3, 24%), thrombocytopenia (any-grade, 29%; grade ≥3, 21%), white blood cell count decrease (any-grade, 24%; grade ≥3, 13%) fatigue (any-grade, 15%; grade ≥3, 0%), pneumonia (any-grade, 13%; grade ≥3, 7%), cough (any-grade, 12%; grade ≥3, 0%), hypogammaglobulinemia (any-grade, 12%; grade ≥3, 0%), and upper respiratory tract infection (any-grade, 10%; grade ≥3, 3%).

AEs that were present for 6 months or greater post-infusion included anemia (any-grade, 19%; grade ≥3, 6%), neutropenia (any-grade, 21%; grade ≥3, 16%), thrombocytopenia (any-grade, 21%; grade ≥3, 13%), white blood cell count decrease (any-grade, 18%; grade ≥3, 9%) fatigue (any-grade, 15%; grade ≥3, 0%), pneumonia (any-grade, 9%; grade ≥3, 6%), cough (any-grade, 10%; grade ≥3, 0%), hypogammaglobulinemia (any-grade, 10%; grade ≥3, 0%), and upper respiratory tract infection (any-grade, 7%; grade ≥3, 1%).

AEs that occurred between the last data cutoff and the current data cutoff included neutropenia (any-grade, 9%; grade ≥3, 9%), infection (any-grade, 7%; grade ≥3, 1%), anemia (any-grade, 4%; grade ≥3, 1%), neurologic event (any-grade, 3%; grade ≥3, 1%), and thrombocytopenia (any-grade, 3%; grade ≥3, 3%).

Additional results confirmed that CAR T-cell expansion is required to derive a response with brexucabtagene autoleucel, showing that peak CAR T-cell expansion was higher in patients with an ongoing response at 12 months or those who relapsed at 12 months vs that in nonresponding patients.

Of 57 efficacy-evaluable patients with data available at baseline, 48 (84%) had detectable B cells at baseline. Among patients with ongoing responses at 12 months, B-cell recovery increased over time and gene-marked CAR T cells decreased over time. There was no observed association between CAR T-cell expansion measured within 2 weeks post-infusion and B-cell aplasia.

“The pharmacological findings in ZUMA-2 point to different mechanisms responsible for primary and secondary treatment failure in relapsed/refractory MCL,” concluded Wang.

References

1. Wang ML, Munoz J, Goy A, et al. One-year follow-up of ZUMA-2, the multicenter, registrational study of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma. Presented at: 2021 EBMT Annual Meeting; March 14-17, 2021; virtual. Abstract OS19-4.

2. Wang ML, Munoz J, Goy A, et al. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in patients (pts) with relapsed/refractory (r/r) mantle cell lymphoma (MCL): results of the phase 2 zuma-2 study. Blood. 2019;134(suppl 1):754. doi:10.1182/blood-2019-126064