Brexucabtagene Autoleucel Provides New Option for Patients With R/R MCL

Javier L. Munoz, MD

Brexucabtagene autoleucek (KTE-X19; TECARTUS) induced durable response in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), according to findings from the phase 2 ZUMA-2 trial (NCT02601313), leading to an FDA approval for use in this patient population on July 24, 2020.

The therapy is a CD19-directed genetically modified autologous T-cell immunotherapy that binds to CD19-expressing cancer cells and normal B cells. Investigators enrolled 74 patients into the ZUMA-2 trial to explore the safety and efficacy of brexucabtagene autoleucel. All enrolled patients underwent leukapheresis, and 68 received the study drug. Overall, 87% of patients had an objective response, including complete responses in 62% of patients.

Javier L. Munoz, MD, MS, director of the lymphoma program at Mayo Clinic in Phoenix, Arizona, and a coauthor on the ZUMA-2 trial, said patients with R/R MCL face “an ominous prognosis,” but one that can hopefully be averted by the use of cellular therapies. In an interview with OncologyLive®, he discussed the efficacy of brexucabtagene autoleucel compared with existing treatments, safety concerns with chimeric antigen receptor (CAR) T-cell agents, and future investigations into this therapy.

OncLive: What was noteworthy about the patient response data from ZUMA-2, particularly across patient subgroups?

High-risk features heralding poor prognosis and refractoriness to standard chemotherapy [for patients with R/R MCL] include high Ki-67, TP53 aberrations, and blastoid/pleomorphic variants. Interestingly, patients with high-risk features such as a TP53 mutation did seem to respond to brexucabtagene autoleucel, which could potentially open a pathway to help this group of patients, fulfilling a historically unmet need.

What is the mechanism of action for this therapy?

CAR T-cell therapies typically use a viral vector to genetically modify the T cells, reeducating them to seek and destroy a particular antigen present on tumor cells. Tisagenlecleucel [Kymriah] and axicabtagene ciloleucel [Yescarta] are approved by the FDA for patients with R/R aggressive B-cell lymphoma who express CD19, which is present in multiple B-cell malignancies. Lisocabtagene maraleucel is under evaluation in the same setting.

Brexucabtagene autoleucel is also an anti-CD19 CAR T-cell agent. That said, brexucabtagene autoleucel is peculiar in that there is an extra step in the manufacturing process to remove circulating CD19-expressing malignant cells in order to decrease the chances of exhaustion of anti-CD19 CAR T cells. T cells are collected from the patient, modified genetically in the laboratory, then reinfused in the patient. There these reinvigorated CAR T cells develop expansion—they have been called a “living drug”—then target malignant cells expressing CD19 for destruction.

What is important to know about cytokine release syndrome and neurological toxicity, both of which are included in the black box warning?

These novel cellular technologies are not for the faint of heart, as severe toxicities including death have been reported. Similar to the CAR T cells currently available for R/R aggressive B-cell lymphomas, serious adverse effects were reported in ZUMA-2. These included grade 3 or higher cytokine release syndrome in 15% of patients and grade 3 or higher neurologic events in 31%.

It takes a village to prescribe these cellular therapies safely, and we are grateful to count on an outstanding multidisciplinary team, which includes neurology, cardiology, infectious diseases, and intensive care that support us as needed through this journey. There were only 2 grade 5 infections in ZUMA-2, which is a testament that only a small minority of patients face lethal toxicities.

How does this therapy fit into the R/R MCL treatment paradigm?

The ZUMA-2 trial inclusion criteria required patients to have prior BTKi [Bruton tyrosine kinase inhibitor] exposure to be eligible. Patients could have received 2 to 5 previous therapies. We know that the outcomes are very dismal for patients with MCL who relapse or who are refractory to treatment with BTKi—overall survival is measured in months. Brexucabtagene autoleucel is indicated for adult patients with R/R MCL. This incongruence between the inclusion/exclusion criteria and the label means that there is potentially a discrepancy in second line when it comes to previous exposure to BTKi.

It goes without saying that we will certainly follow the FDA-approved label for brexucabtagene autoleucel and will consider it for any adult patient with R/R MCL, including patients with high-risk features. That said, not every patient with R/R MCL may be able to receive CAR T cells due to performance status, comorbidities, or lack of social support or a caregiver. One size does not fit all, particularly in such a heterogeneous disease as MCL.

What are the next steps for brexucabtagene autoleucel?

We need to embrace clinical trials that allow prior CAR T-cell failure. Next steps for autologous CAR T cells include decreasing manufacturing time, improving the safety profile, addressing the feasibility of outpatient administration, and testing CAR T cells in earlier lines of therapy. For example, tisagenlecleucel and axicabtagene ciloleucel are currently available for patients with aggressive lymphomas in the R/R setting; nevertheless, investigators are studying CAR T cells in the second line and frontline. It would not be unexpected to see brexucabtagene autoleucel assessed in earlier lines of therapy for MCL.

The TRANSCEND-NHL-001 trial [NCT02631044] evaluated lisocabtagene maraleucel in several subtypes of lymphomas, including patients with R/R MCL, and I am excited to see data regarding CAR T cells in MCL. Additionally, allogeneic CAR T cells are under evaluation in clinical trials that will, hopefully, provide off-the-shelf cellular therapies that will bypass any delays seen during manufacturing. Finally, there are multiple trials addressing autologous and allogenic cellular therapies in R/R MCL, and we await those results with enthusiasm.