ZUMA-18 Study Shows Brexu-cel's Therapeutic Potential in MCL

Andre Goy, MD

Brexucabtagene autoleucel (brexu-cel; Tecartus), the autologous chimeric antigen receptor (CAR) T-cell therapy, demonstrated efficacy when evaluated in the expanded access ZUMA-18 study (NCT04162756) in patients with relapsed/refractory mantle cell lymphoma (MCL).

Previously, brexu-cel was studied in the phase 2 ZUMA-2 trial (NCT02601313) for patients with MCL where the CAR T-cell therapy improved safety outcomes. Findings from the 23 patients with relapsed/refractory MCL enrolled in the ZUMA-18 study were consistent with what was observed in ZUMA-2. At a median follow-up of 33.5 months, the investigator-assessed objective response rate was 87% (95% CI, 66.4%-97.2%), and 57% of patients had a complete response (CR; 95% CI, 34.5%-76.8%). Additionally, 30% of patients had a partial response (95% CI, 13.2%-52.9%), and 9% of the best responses were progressive disease (PD; 95% CI, 1.1%-28.0%).

At the data cutoff date, the median overall survival (OS) was not reached (95% CI, 10.4 months-not estimable) with a 58% OS rate at 24 months. At this time, 61% of patients were still alive while 9 patients (39%) had died, including 5 due to AEs, 2 due to PD, and 2 due to other causes.

For safety, all 23 patients who received brexu-cel in the expanded access study had at least 1 grade ≥3 adverse event (AE). One patient (4%) had grade ≥3 cytokine release syndrome, and 8 patients (35%) experienced a neurological event. Further, there were 5 AEs determined to be grade 5. Of these AEs, 1 was related to brexu-cel while the other 4 were deemed unrelated to the CAR T-cell therapy.

In an interview with Targeted Oncology_^TM, Andre Goy, MD, physician-in-chief, Hackensack Meridian Health Oncology Care Transformation Services, and chairman, chief physician officer, chief, Lymphoma Division, John Theurer Cancer Center, Hackensack University Medical Center, discussed the potential of brexu-cel for the treatment of patients with relapsed/refractory MCL and how these 2 studies provide support for use of the agent in this patient population.

Targeted Oncology: Can you discuss the significance of brexu-cel and how it is being studied in MCL?

Goy: Brexu-cel has been game-changing in relapsed/refractory mantle cell lymphoma in patients who are heavily pretreated. On the ZUMA-2 trial, [patients] had to have failed chemotherapy, immunotherapy, an anti-CD20 [agent], and also a [Bruton tyrosine kinase (BTK)] inhibitor. Usually, this patient had a very short survival at 3 to 8 months, depending on the studies. The ZUMA-2 trial was a pivotal trial that led to the approval [of brexu-cel]. ZUMA-18 was opened to expand access for patients with relapsed or refractory mantle cell lymphoma who then could not benefit from this therapy. The trial was designed pretty much with the same design with the patient having to have relapsed/refractory mantle cell lymphoma, at least 1 line of prior therapy, no auto[logous] transplant unless it was [about] 6 months before, no [graft-vs-host disease], and no [central nervous system] involvement. They got the standard bridging therapy if needed with steroids or BTK, and then they also could get therapy if they had rapidly progressive disease, which was a difference from the ZUMA-2 trial.

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Who was included in the ZUMA-18 trial and how did this compare with enrollment on ZUMA-2?

There were 2 cohorts. The first cohort was to look at patients who were waiting for the commercial approval of CAR T to potentially get benefit, and that is the benefit of these expanded access trials. Cohort 2 was for patients who had a product whose manufacturer was outside of the specification based on the FDA threshold of the viability of 80%. The goal was to evaluate safety, response rates, survival, etc. We had 23 patients enrolled, [including] 21 in cohort 1 and 2 in cohort 2. These patients were different from ZUMA-2 in the fact that they were older for median age 69 vs 64-65. They were more heavily pretreated with a median of 4 prior therapies, and 60% had an ECOG of 1, which was 35% in ZUMA-2. [These were] sicker and older patients [who were] more heavily pretreated.

What were the findings from the ZUMA-18 study?

The response rate was still very impressive, and then the CR rate was 57%. The median duration of response was a bit shorter. ZUMA-2 was a more difficult population [that was] more heavily pretreated. There were no new safety signals. What was interesting in this trial is that with a long-term follow-up at 3 years, median overall survival was 58% for 3 years. This is an important aspect. These patients didn't really have an option, and most of them have not qualified for the ZUMA-2. This confirms the efficacy, the benefit of the ZUMA-2 trial, which I also updated with long-term, 4-yearfollow-up.

For the patient who achieved a CR, with a 4-year follow-up, the median overall survival was almost 5 years. This is a patient population that would have had very little options outside of a potential allogeneic transplant. ZUMA-18 also showed activity in spite of it being older, more heavily pretreated, and sicker patients.

What do these findings mean for patients with MCL and their clinicians moving forward?

There has been data on real-world outcomes on CAR T-cell therapy and brexu-cel, showing the similar response rate and CR. What's exciting is that the traditional prognostic factors don't have a lot of impact on the responses, [progression-free survival], and duration of response. The biggest question is who is benefiting from this therapy? We want to know that. There are other studies that are trying to identify this by looking at biomarkers from the patients themselves or clinical prognostic factors like age, comorbidities, sicker patients, more fatigue, [etc.].

There [was] interesting data at [the American Society of Hematology 2023 Annual Meeting], looking at a patient who will actually do better when they have more B cells prior to CAR T, and also have a better T-cell profile and [absolute lymphocyte count] over [absolute monocyte count] as a marker of immunosuppressive status. That seems to be very important. [There are] markers that are related to the tumor, the bulk, and the [lactated dehydrogenase]. And [there are] markers that are related to the product. What's the proportion of T-cell memory-naive cells, and not too much of a differentiated profile because they're not going to expand as well. Then post-infusion, what's the most critical factor across all the studies in CAR T, not surprisingly, is the peak that you get in area under the curve. That is important, because if we could monitor this more carefully, [this is] 1 thing that could potentially combine with additional therapy to try to boost this human response because once it works, it's efficient.

On ZUMA-2 to trial, there [were] only 3 relapses after 24 months. If you have a CR, it's quite durable. We want to move forward to try to understand how we predict and understand who should benefit from this therapy. [There are] 2 big questions in oncology and only 2 questions that fit perfectly into the paradigm. The first is, what's my best option now? Obviously, a patient deserves this, but we need assistance to understand what's the best sequence of care. [Also,] for the high-risk patients, we will likely move the CAR T earlier as we see more durable responses and a higher CR rate.

What should a community oncologist know about the current field of MCL?

First, clinical trials are what has brought us where we are. The expanded access trial is something that I think is great because it gives patients an opportunity that they would not have because most of them would not have qualified for the trial. [Another] aspect is to refer patients early when it comes to complicated or difficult diseases, because it's always easier to treat someone earlier.

There's nothing that can cure relapsed/refractory MCL outside of CAR T. There's a lot of great drugs out there and I'm very interested in them. We have BTK second-generation, third-generation, noncovalent with very impressive durable responses, but they don't cure anyone yet. There are also bispecifics that seem interesting and I think they will be more in a frontline setting and help develop non chemotherapy options or consolidation in [minimal residual diease]MRD-positive patients. There was a lot of concern in the beginning with CAR T toxicity. We have learned how to manage and are pre-emptive with toxicity. I haven't seen a patient in the [intensive care unit] with CAR T in a long time. Now if we refer patients earlier, they have a 1 and done treatment and we should all go for this.

REFERENCES:

Goy A, Jacobson CA, Flinn IW, et al. Outcomes of patients with relapsed/refractory mantle cell lymphoma (R/R MCL) treated with brexucabtagene autoleucel (Brexu-cel) in ZUMA-2 and ZUMA-18, an expanded access study. December 5-9, 2023; San Antonio, TX; abstract 106.