Real-World Analysis Shows Brexu-Cel Elicits Higher CR Rate in Patients With R/R MCL Given Fewer Lines of Prior Therapy

In a real-world study, the CAR T-cell therapy brexucabtagene autoleucel (brexu-cel; Tecartus) elicited a higher complete response (CR) rate in patients with relapsed/refractory mantle cell lymphoma (MCL) who received 1 or 2 prior lines of therapy vs those given 3 or more prior lines of therapy, pointing to a potential benefit for the use of brexu-cel in earlier lines of treatment, according to Nausheen Ahmed, MD.

Data from the real-world study of patients registered in the Center for International Blood and Marrow Transplant Research (CIBMTR) observational database presented at the 2023 EHA Congress and the 2023 ASCO Annual Meeting showed that brexu-cel produced consistent outcomes, regardless of prior treatment with bendamustine, a prior BTK inhibitor, or prior autologous stem cell transplant [ASCT].^1,2

At a median follow-up of 12.0 months (range, 0.0-25.3) for the overall evaluable population (n = 380), the overall response rate (ORR) was 90% with a CR rate of 78%. ORRs were similar for patients who did or did not receive a prior BTK inhibitor (90% vs 92%), those who did or did not receive prior bendamustine (89% vs 92%), and patients who did or did not undergo prior ASCT (91% vs 90%). Notably, patients who received 1 to 2 prior lines of therapy experienced an ORR of 94% with a CR rate of 88%, compared with an ORR or 89% with a CR rate of 76% for those given 3 or more prior lines of therapy.

The FDA approved brexu-cel for adult patients with relapsed/refractory MCL in 2020, based on findings from the phase 2 ZUMA-2 trial (NCT02601313).³ Ahmed noted that the overall population of the real-world study was similar to that of ZUMA-2, and efficacy and safety data were comparable between the 2 studies.

“This is the largest real-world analysis to date looking at the effectiveness and safety data for brexu-cel in a real-world population. We saw that the outcomes were fairly similar to the ZUMA-2 outcomes, although the follow-up [for the real-world study] was short at 12 months, so we do not have mature data on median overall survival [OS] and progression-free survival [PFS],” Ahmed explained in an interview with OncLive.^®

In the interview, Ahmed explained the rationale for examining real-world outcomes observed with the use of brexu-cel in the treatment of patients with relapsed/refractory MCL, detailed the key efficacy and safety findings from the overall population and different subgroups, and discussed what will be gained with longer follow-up of the study. Ahmed serves as an assistant professor of Hematologic Malignancies and Cellular Therapeutics at the University of Kansas Medical Center, in Kansas City.

OncLive: What were the goals of this study of real-world outcomes patients with relapsed/refractory MCL who were treated with brexu-cel?

Ahmed: This study is an effort looking at the CIBMTR data. It's a subgroup analysis of the post-authorization safety study for brexu-cel in the United States. It's a non-interventional, prospective cohort study aiming to describe long-term safety and efficacy outcomes of brexu-cel in patients with relapsed/refractory MCL.

The target enrollment was 500 patients, which was reached in December 2022. Some of these patients are still being followed up, and the follow-up will continue for 15 years. This [analysis] is a first look at the outcomes and efficacy. We have a total of 380 patients who we included in the analysis for safety and efficacy.

What was the rationale of looking at how prior treatments may affect outcomes for patients who go on to receive brexu-cel?

Brexu-cel has been approved in the United States and in Europe based on the ZUMA-2 analysis. ZUMA-2 enrolled patients who had prior [exposure to] bendamustine, an anthracycline, and a BTK inhibitor.

When the drug was approved in the United States, it was approved in the second-line setting, without any requirement for a prior BTK inhibitor or any [specific] therapy, as long as the patient had received 1 prior line of therapy. In Europe, the indication is after 2 lines of therapy and prior BTK inhibitor exposure. Hence, there's a need to understand the real-world outcomes in patients who may have been BTK inhibitor naïve and in patients who were not exposed to bendamustine. There is also controversy surrounding whether bendamustine exposure would reduce the efficacy of CAR T-cell therapy, so we wanted to get a better idea of [outcomes] for these groups.

We also looked at patients who had prior [ASCT] vs no prior [ASCT]. An area of interest was looking at patients [who received] fewer lines of therapy: 1 to 2 lines of therapy vs 3 or more lines of therapy.

How did the characteristics of the patient population from the real-world study compare with the population enrolled in ZUMA-2?

We looked at baseline patient characteristics in the whole cohort. We found that it was, broadly speaking, quite similar to the ZUMA-2 population. The median age was 66.8 years compared with 65 years for ZUMA-2. There were patients in this [real-world] cohort who had extranodal central nervous system disease, TP53 deletions, and a Ki-67 [proliferation index] of 50% or more. We looked at those subgroups. [Patients received a] median of 4 [prior] lines of therapy. Although [the real-world study] was not a head-to-head comparison with ZUMA-2, [the populations] were quite similar.

When we looked at the subgroups for baseline patient characteristics, we found that older patients were more likely to have received a prior bendamustine and less likely to receive prior [ASCT]. Patients with no BTK inhibitor exposure tended to receive brexu-cel in earlier lines and were less likely to receive bridging therapy.

What were the key efficacy findings presented at the 2023 EHA Congress and the 2023 ASCO Annual Meeting?

The ORR in this [real-world] cohort was 90% with a CR rate of 78%. This is, again broadly speaking, similar to the ZUMA-2 response rates. When we looked at subgroups based on BTK inhibitor exposure, bendamustine exposure, and [ASCT] vs no [ASCT], we found that these outcomes of CR and ORR were fairly similar regardless of [these prior treatments]. One interesting finding is that the CR rates were significantly better in patients who had fewer prior lines of therapy [88%] compared with those who had 3 or more prior lines of therapy [76%].

When we looked at the duration of response [DOR], the 12-month DOR rates for patients who achieved CR was 69%. For all responders—those who had achieved CR or PR—the DOR rate at 12 months was 64%. The median DOR was [21.7] months, but we have to understand that the follow-up is very short. We have only a 12-month median follow-up, so this is likely to change, and we will see as data mature.

With the short follow-up of 12 months in this population, we saw a 12-month PFS [rate] of 61%, and the 12-month OS rate was 74%. We also looked specifically at the cumulative incidence of relapse, and at 12 months, 31% of patients had relapsed.

Regarding safety, what were the key findings from the overall population, and were there any key differences between the subgroups?

For safety, we looked at the incidence of cytokine release syndrome [CRS] and immune effector cell–associated neurotoxicity syndrome [ICANS] in the overall population, which was very similar to the ZUMA-2 data. Eighty-eight percent of the patients experienced any-grade CRS, with a 10% being grade 3 or higher. Sixty percent of patients experienced any-grade ICANS, with 28% being grade 3 or higher. The median time to onset of CRS was 5 days, and the median time to onset of ICANS was 7 days. Broadly speaking, this was comparable with ZUMA-2 outcomes.

We looked at other safety outcomes. We found that 21% of the patients had prolonged thrombocytopenia and 6% had prolonged neutropenia. This was defined as thrombocytopenia and neutropenia at the 30-day mark. Infections [occurred in] 41% of [patients], which included bacterial infections, viral infections, COVID-19, and fungal infections.

We then looked at cause of death and non-relapse mortality. Non-relapse mortality was 4% at day 100 and 8% at 1 year. When we looked at causes of death, by far, the most common reason for death was disease relapse [14%]. However, looking at other causes not related to disease relapse, the next most common was infection [3%].

We did a multivariate regression analysis to look at the subgroups and associations with grade 3 or higher CRS, ICANS, prolonged neutropenia, prolonged thrombocytopenia, and non-relapse mortality. We found that those with prior bendamustine exposure tended to have less high-grade ICANS, but they had more risk of prolonged cytopenias. Patients with 1 to 2 prior lines of therapy tended to have higher grade CRS, and this may be explained by T-cell fitness.

What are the potential implications of these real-world findings?

The CR rates were higher in patients who received 1 to 2 lines of therapy vs those who received 3 or more lines of therapy, which suggests that earlier use [of brexu-cel] might be beneficial for patients. However, in our data set, this has not yet translated into OS or PFS benefits, and we need longer follow-up to look at that.

We also noted that outcomes of patients with relapsed/refractory MCL [treated with] brexu-cel were largely consistent throughout all subgroups. Whether patients are BTK inhibitor naïve, received prior bendamustine, or received prior [ASCT], all such patients derived a similar benefit from brexu-cel.

References

1. Ahmed N, Kambhampati S, Hamadani M, et al. Real-world outcomes of brexucabtagene autoleucel (brexu-cel) for relapsed or refractory mantle cell lymphoma: a CIBMTR subgroup analysis by prior treatment. Presented at: 2023 European Hematology Association Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S220.
2. Kambhampati S, Ahmed N, Hamadani M, et al. Real-world outcomes of brexucabtagene autoleucel (brexu-cel) for relapsed or refractory (R/R) mantle cell lymphoma (MCL): a CIBMTR subgroup analysis by prior treatment. J Clin Oncol. 2023;41(suppl 16):7507. doi:10.1200/JCO.2023.41.16_suppl.7507
3. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. News release. FDA. July 24, 2020. Accessed July 19, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-mantle-cell-lymphoma