Real-World Outcomes With Brexu-Cel Are Consistent With Clinical Data in R/R MCL, Regardless of Prior Treatment

Response rates and toxicities observed with brexucabtagene autoleucel (Tecartus; brexu-cel) in patients with relapsed/refractory mantle cell lymphoma (MCL) appear comparable between clinical practice and a clinical trial setting irrespective of prior treatment type, according to Swetha Kambhampati, MD. She added that the data warrant continued efforts to better contextualize response rates in relation to the long-term benefit of the agent in this disease.

Initial findings from a CIBMTR observation database subgroup analysis of patients with heavily pretreated MCL were presented at the 2023 ASCO Annual Meeting. At a median follow-up of 12 months, brexu-cel produced an overall response rate (ORR) of 90% in the overall population; this included a complete response (CR) rate of 78%. The median duration of response was 21.7 months (95% CI; 14.8-not evaluable). Moreover, a multivariate analysis of efficacy outcomes according to treatment type revealed that responses with brexu-cel were not significantly hampered by prior exposure to standard-of-care therapies like BTK inhibitors or bendamustine.¹

“There may [also] be a signal [for] higher response rates and increased likelihood of achieving a CR in patients who received the agent in earlier lines of therapy, which needs further evaluation,” noted Kambhampati, who is a hematologist/oncologist and assistant professor in the Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, at City of Hope in Duarte, California, in an interview with OncLive^®. 

Response rates in the subgroup analysis were comparable to those observed in the phase 2 ZUMA-2 trial (NCT02601313), in which brexu-cel induced an ORR of 91% with a CR rate of 68%.1 These data supported the FDA approval of brexu-cel in this population on July 24, 2020.²

In the interview, Kambhampati explained the need for real-world data on responses to brexu-cel in patients with relapsed/refractory MCL, compared safety and efficacy data from the subgroup analysis with prior results from ZUMA-2, and discussed how these findings support more long-term follow-up in this population. 

OncLive: Why was it important to elucidate and compare the safety and efficacy of brexu-cel in clinical practice with outcomes in clinical trials for patients with MCL?

Kambhampati: The only CAR T-cell product currently FDA approved in relapsed/refractory MCL is brexu-cel. [Findings from] the pivotal ZUMA-2 trial led to [the agent’s] approval in 2020. We know that clinical trials often have selective eligibility criteria, so it’s important to evaluate real-world safety and efficacy outcomes [with] brexu-cel. That was the aim and objective of this study. In addition to evaluating real-world outcomes with brexu-cel, we also aimed to evaluate how outcomes are impacted by [the type of] prior treatment [regimen], namely bendamustine, BTK inhibitors, and autologous stem-cell transplant [ASCT].

Could you briefly discuss key data from ZUMA-2 that supported the FDA approval of brexu-cel in this population?

ZUMA-2 showed high response rates and high CR rates [with brexu-cel] in patients with relapsed/refractory MCL. Of note, all patients enrolled in ZUMA-2 had been exposed to a prior BTK inhibitor, but the FDA label does not specify prior treatments. That was one of the things [we wanted] to look at in this real-world study, because there could be heterogeneity in clinical practice. [In] ZUMA-2, there were high rates of immune effector cell–associated neurotoxicity syndrome [ICANS] and cytokine release syndrome [CRS, as well as] some infections. Overall, the data [still] looked good and led to the approval of the product. Our goal was to see how this translates to a real-world population.

Please describe the patient population included in the real-world subgroup analysis.

We had 380 patients [enrolled onto] our study, and data were extracted from the CIBMTR registry, which is a non-international registry. This study [involved] 84 centers across the United States, and patients were enrolled from July 2020 to December 2022. All the patients received brexu-cel.

[Notably,] the overall cohort was a heavily pretreated population. The median prior lines of therapy [received] was 4 and ranged from 1 to 12. Twenty percent of patients [had] TP53/17p deletion, and 40% of patients [had] high Ki67. This [population] reflected [those treated in] real-world practices in terms of high-risk and heavily pretreated patients.

What was revealed in terms of real-world safety and efficacy outcomes with brexu-cel?

In the overall cohort, the ORR was 90%, and the CR rate was 78%. The median DOR was 21.7 months. The important toxicities of interest were CRS and ICANS. Overall, any-grade CRS and ICANS [rates were] 88% and 60%. High-grade [CRS and ICANS rates were] 10% and 28%, respectively. These outcomes are all very comparable to those reported in ZUMA-2, which is reassuring.

[Additionally,] patients who received prior bendamustine did have a reduced risk of high-grade ICANS and prolonged thrombocytopenia. Patients who received 1 to 2 prior lines compared with [3 or more lines] had a higher [incidence of] grade 3 or higher CRS, so there were some signals that need further evaluation.

We also looked at how prior treatments impact outcomes, including prior lines of therapy. We found that response rates were higher in patients when they received 1 to 2 prior lines compared with 3 or more. We did a multivariate analysis and adjusted it for baseline characteristics like age, sex, and other disease characteristics. We found that [previous] exposure to a prior BTK inhibitor or bendamustine did not [affect] efficacy and safety outcomes. Patients who had received prior ASCT had improved progression-free survival [PFS], and patients who had received only 1 to 2 prior lines compared with 3 or more had two-fold higher odds of achieving a CR.

What was reassuring was [that] comparable safety and efficacy outcomes in this heavily pretreated high-risk patient population reflected real-world patient populations in clinical practice, as well as the fact that exposure to prior treatments did not [majorly] affect safety and efficacy.

Do these findings support the potential use of brexu-cel in earlier lines of therapy in MCL?

In this largest real-world study to date, findings support [efforts to] use brexu-cel in earlier lines because we saw higher response rates in patients who were less heavily pretreated. Even when adjusting for other baseline characteristics, [such as] differences in both subgroups [or the number of] prior lines [received], multivariate analysis [revealed] a higher likelihood of achieving a CR in patients who [received] 1 to 2 prior lines. This suggests that using this therapy earlier may improve outcomes. Of course, this needs further evaluation, but it’s mechanistically reasonable, as patients [who are] less heavily pretreated have improved T-cell quality. This may impact outcomes with brexu-cel.

Are there any specific next steps planned for this research?

The current study reports a 12-month follow-up period, but we need more long-term follow-up to address how durable these responses are, how they translate in terms of overall survival and PFS, and [how they] compare with 3-year follow-up data from ZUMA-2. We’d like to continue evaluating these outcomes with longer follow-up in a larger sample size [for] some of the [patient] subgroups, such as those who are BTK inhibitor naïve. [We also want] to look at some of the granular details further, including how additional disease characteristics [or] additional details like timing from prior bendamustine to leukapheresis affect outcomes.

What does this research signify about the potential real-world efficacy of other emerging CAR T-cell products in MCL?

This is the largest real-world study [of brexu-cel in MCL]. This is currently the only CAR T-cell product approved [for this disease]. However, there are data coming out for lisocabtagene maraleucel [Breyanzi] in relapsed/refractory MCL from the [phase 1] TRANSCEND NHL 001 trial [NCT02631044]. We are eagerly awaiting full details on those results, and we’ll need to [validate the data from] each trial in a real-world patient population.

What other presentations at the 2023 ASCO Annual Meeting did you find particularly interesting or practice-changing within hematologic malignancies?

It was a big day in terms of the plenary [session]. Alex Herrera, MD, of City of Hope, presented [findings from the phase 3] SWOG S1826 trial [NCT03907488] looking at nivolumab [Opdivo] and [doxorubicin, vinblastine, and dacarbazine; AVD] compared with brentuximab vedotin [Adcetris] and AVD. [Results] showed an improvement in PFS and some reduced toxicity [with nivolumab plus AVD]. [These are] early data, but they are really promising. I think that’s a huge, practice-changing study that could really [improve] the treatment paradigm for patients with advanced Hodgkin lymphoma.

We [also saw] a host of exciting studies in chronic lymphocytic leukemia, MCL, and follicular lymphoma [in the] lymphoma abstract session.

Dr Kambhampati had no relationships to disclosure.

References

1. 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
2. US FDA approves Kite’s Tecartus, the first and only CAR T treatment for relapsed or refractory mantle cell lymphoma. News Release. Gilead Sciences. July 24, 2020. Accessed August 2, 2023. https://www.gilead.com/news-and-press