Michael Wang, MD, discusses the FDA approval of brexucabtagene autoleucel in mantle cell lymphoma and ongoing research aimed at optimizing the safety and persistence of the product.
The FDA approval of brexucabtagene autoleucel (Tecartus; formerly KTE-X19) marks a significant milestone for the field of mantle cell lymphoma (MCL), according to Michael Wang, MD.
On July 24, 2020, the FDA approved the CD19-directed CAR T-cell therapy for the treatment of patients with relapsed/refractory MCL, based on findings from the phase 2 ZUMA-2 trial.
In the trial, patients who had received a median 3 prior lines of therapy experienced an objective response rate of 87% and a complete response (CR) rate of 62% with a single infusion of the CAR T-cell product.
“As we know, the natural history of MCL is a repeated pattern of remission and relapse. After a few relapses, the patient has a very small chance of responding to any therapy. However, in the ZUMA-2 trial, we saw really dramatic and unprecedented efficacy with brexucabtagene autoleucel in the relapsed setting,” said Wang, lead study author of the pivotal trial.
In the primary efficacy analysis, which was presented during the 2019 ASH Annual Meeting, the median progression-free survival (PFS) had not been reached. The 12-month PFS rate was 61%. The median overall survival (OS) had also not been reached, with a 12-month OS rate of 83%.
Regarding safety, all-grade cytokine release syndrome (CRS) and neurotoxicity occurred in 91% and 63% of patients, respectively. CRS was well managed with tocilizumab (Actemra; 59%) or corticosteroids (22%). The median time to onset was 2 days, and the median duration was 11 days. Neurotoxicity was managed with tocilizumab (26%) and corticosteroids (38%), and the median time to onset was 7 days with a median duration of 12 days.
Grade 3 or greater CRS and neurologic events occurred in 18% and 37% of patients, respectively.
“The FDA approval of brexucabtagene autoleucel will change the way we treat patients with relapsed MCL forever and for the better,” said Wang.
In an interview with OncLive, Wang, a professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, discussed the FDA approval of brexucabtagene autoleucel in MCL and ongoing research aimed at optimizing the safety and persistence of the product.
OncLive: What is the current state of treatment in MCL?
Wang: MCL is a young disease. In 1992, the MCL was used to do identify this group of patients. Before 1992, we referred to MCL with different categories and different names. In the first era of MCL treatment, we used high-dose and regular-dose chemotherapies. Unfortunately, these treatments were not curative, and patients inevitably relapsed.
Then we started using targeted therapies, such as ibrutinib (Imbruvica), acalabrutinib (Calquence), zanubrutinib (Brukinsa), lenalidomide (Revlimid), bortezomib (Velcade), and venetoclax (Venclexta). We know that these targeted agents are great. They’re able to put some patients in long-term remission, but even these agents are not curable. The majority of these patients will relapse and become resistant to chemotherapy and targeted therapy. These patients have very aggressive disease. After BTK therapy, patients’ OS is only about 6 to 10 months.
Brexucabtagene autoleucel has dramatically changed patients’ OS. The median OS in the ZUMA-2 trial has not been reached after about 1 to 2 years. We are going to report the longer-term follow-up analysis of the ZUMA-2 trial at the 2020 ASH Annual Meeting. It’s clear that treatments are accelerating in MCL. The dream to cure MCL has never been so close.
What does the approval of brexucabtagene autoleucelbring to patients with MCL?
On behalf of my colleagues, I want to congratulate all the patients for having access to this great therapy.
As the overall principal investigator of this international clinical trial, I have to say it’s really a privilege and an honor to have worked with all the colleagues and especially the patients and their families on this trial.
In this study, patients had received 3 prior therapies, so brexucabtagene autoleucel was the fourth therapy patients received. In the fourth-line setting, generally the response rate is about 20% to 25%. With the CD19-directed CAR T-cell therapy, the response rate is 87%, and the CR rate is 62%.
What can you tell us about the onset of CRS and neurotoxicity?
The [rate of] CRS and the neurotoxicity is very favorable. The CRS usually occurs after about 1 or 2 days and peaks after about a week. The neurotoxicity peaks at around day 10 to day 14.
In the ZUMA-2 trial, the CRS and the neurotoxicity were very well managed. Though, 1 patient died from CRS. Historically, we have always been concerned about CRS. Patients can have a hard time with hypotension and high fevers. Now, we have so many therapies to support us, including early use of steroids such as tocilizumab.
One patient had severe neurotoxicity, so we gave high-dose steroids, intrathecal cytarabine and steroids, and ventriculostomy where you drill a hole into the cranium and let the pressure out. We used rabbit antithymyocyte globulin which saved the patient from cerebral edema. We reversed it, and now the patient is in CR at work without any residual neurotoxicity. This is a remarkable example of CAR T-cell therapy toxicity management and prolonged efficacy.
Where would you like to focus future research efforts?
CAR T-cell therapy is still a very new therapy in the field of MCL. We’re still trying to figure out many things. In the ZUMA-2 trial, we found that certain cytokines are associated with the efficacy and the toxicity of the product. Therefore, we want to use different measures to enhance the efficacy and reduce the toxicity using cytokine and chemokine profiling.
We’ll also need to study minimal residual disease. Only 60 patients were [included in the primary analysis of] the ZUMA-2 trial, so we’ll need to study more samples in a controlled setting to understand the relationship between cytokines and CRS and neurotoxicity. We also want to know how long CAR T cells can persist. Some patients have CAR T-cell persistence 1 year after receiving therapy, but we want even longer timepoints.
We also want to study the microenvironment of the tumor. The tumor and the CAR T-cell therapy constantly change, but so does the microenvironment. In my laboratory, using RNA sequencing together with DNA methodologies, we reported at the AACR Virtual Annual Meeting how to decipher this evolution in not only the tumor cells, but also the tumor microenvironment. In the future, we also want to follow the CAR T cells to see what happens to them. It is a new but exciting and promising field. My hope is that CAR T-cell therapy will cure a fraction of patients with MCL.