Brexu-Cel Shows Comparable Outcomes With ZUMA-2 in Real-World MCL

Brexucabtagene autoleucel (brexu-cel; Tecartus), the first FDA-approved chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory mantle cell lymphoma (R/R MCL), showed safety and efficacy outcomes consistent with the ZUMA-2 trial (NCT02601313) in a real-world population with more high-risk features.¹

Among 168 patients with R/R MCL across 16 US Lymphoma CAR T Consortium centers who received a brexu-cel infusion, the best objective response rate (ORR) was 90% and the complete response (CR) rate was 82%. Multiple high-risk disease features were associated with poor progression-free survival (PFS), as was prior exposure to bendamustine (Bendeka).

Brexu-cel, an anti-CD19 autologous CAR T-cell therapy, was granted accelerated approval in patients with R/R MCL based on the results of the single-arm phase 2 ZUMA-2 trial.² Patients on ZUMA-2 demonstrated an ORR of 87% and a duration of response (DOR) that was not reached (range, 0-29.2 months) at a minimum follow-up of 6 months.³

In the US Lymphoma CAR T Consortium study, 189 patients underwent leukapheresis between August 1, 2020, and December 31, 2021, to receive brexu-cel as standard-of-care therapy, though 21 did not receive CAR T-cell therapy, primarily due to death (n = 9) or manufacture failure (n = 7).¹ The median age of patients who received brexu-cel was 67 years (range, 34-89), and 128 (76%) patients were male.

In this real-world population, 149 patients (79%) who underwent leukapheresis would not have been eligible for the ZUMA-2 trial. Some of these were due to the ZUMA-2 trial requiring patients not receive prior therapies including anthracycline, bendamustine, or a Bruton tyrosine kinase inhibitor. Patients who were naive to one or more of these made up 14% of the real-world population.

However, 65% of patients would have been ineligible for ZUMA-2 due to disease status or comorbidities including creatinine clearance of less than 60 mL/min (20%), an ECOG performance status of 2 or higher (14%), recurrent disease after more than 5 prior therapies (11%), central nervous system (CNS) involvement (11%) and having significant cardiac disease within 12 months (10%).

Bridging therapies were utilized prior to infusion in 128 patients (68%), including BTK inhibitors and venetoclax (Venclexta). In 95 who were assessed for a response, there was an ORR to bridging therapies of 33%, including 6% with a CR.

At a median follow-up of 14.3 months (95% CI, 12.7-15.9), the median DOR was 17.2 months (95% CI, 14.4-not estimable [NE]). At 6 months, 75% of patients had a continued response (95% CI, 68%-82%) and at 12 months, 65% had a continued response (95% CI, 56%-72%).

The median PFS was 16.4 months (95% CI, 12.7-NE), and the 6-month and 12-month PFS rates were 69% (95% CI, 61%-75%) and 59% (95% CI, 51%-66%), respectively. Median overall survival (OS) was not reached (95% CI, 18.7-NE), with 6-month OS rate of 86% (95% CI, 79%-90%) and 12-month OS rate of 75% (95% CI, 67%-81%).

Patients who had high-risk simplified MIPI (MCL International Prognostic Index) score had a worse PFS than the overall population (HR, 3.82; 95% CI, 1.92-7.59; log-rank P < .001). Other high-risk subgroups also had worse PFS outcomes, including patients with Ki-67% of at least 50%, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant. Those with disease progression within 24 months of primary therapy also had a shorter PFS than overall, but it was not a statistically significant difference.

Patients with CNS involvement, who would have been excluded from ZUMA-2, did not appear to have worse PFS than the overall population. Patients who received BTK inhibitors also did not have a statistically significant difference in PFS from those who were naive to BTK inhibitors. No difference was seen in PFS based on worse performance status or being treatment-naive to bendamustine/anthracycline, but patients who would have been excluded from ZUMA-2 due to disease status or comorbidities did have a worse OS. Finally, response to bridging therapy was not associated with improvement in PFS or OS.

Investigators observed that a 41% of patients who had received bendamustine within 6 months of leukapheresis did not receive brexu-cel, including 13% who had manufacturing failure. Patients who received bendamustine also appeared to have worse outcomes, including lower ORR in those who received brexu-cel. PFS and OS were lower in all patients with recent bendamustine exposure in the intent-to-treat population, but when adjusted for simplified MIPI score and Ki-67, these were not statistically significant.

“These findings appear to be consistent with prior observations regarding the negative impact on T cells of bendamustine,” the investigators stated in their report. “Larger studies are needed to investigate whether recent bendamustine exposure is independently associated with CAR T-cell therapy outcomes.”

In terms of safety, 90% of patients had cytokine release syndrome (CRS), but only 8% of patients experienced grade 3/4, including 1 patient with grade 5 toxicity. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 61%, with grade 3/4 in 32%. This was very similar to the ZUMA-2 trial, in which 91% of patients had CRS, 15% of which was grade 3/4, and 63% of whom had neurologic events, 31% of which was grade 3/4. Intensive care admission was required for 34 patients (20%).

Other significant adverse events included prolonged anemia, thrombocytopenia, and neutropenia lasting up to day 90 of treatment, and infections, which most commonly occurred within 30 days of infusion.

Investigators noted that the outcomes were similar to ZUMA-2 in this real-world population. This included a higher CR rate of 82% versus 62% in ZUMA-2, which they suggested could be explained by a wider range of bridging therapies being utilized or prior therapy being extended, leading to better disease control before infusion. The efficacy of brexu-cel in a patient population with more high-risk features was positive, though there is still a need to improve PFS and OS outcomes for these patients. Those with CNS involvement benefited from therapy and also did not have increased neurotoxicity. Lastly, these data were the first to show efficacy with brexu-cel in patients who were naive to BTK inhibitors.

“In conclusion, this study demonstrated encouraging safety and efficacy results of brexu-cel in standard-of-care practice that were comparable with those in ZUMA-2, supporting continuous and expanded use of brexu-cel for R/R MCL in routine practice,” the investigators stated in their report.

_References:

_{1. Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in standard-of-care practice: results from the US Lymphoma CAR T Consortium. J Clin Oncol. Published online February 8, 2023. doi:10.1200/JCO.22.01797}

_{2. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. FDA. Updated July 27, 2020. Accessed February 13, 2023. https://bit.ly/3k0AptV}

_{3. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347}