Expanding Access to Brexucabtagene Autoleucel for Mantle Cell Lymphoma With Andre Goy, MD
In this interview from the American Society of Hematology (ASH) Annual Meeting, Oncology Data Advisor speaks with Dr. Andre Goy, Chair of the John Theurer Cancer Center and Hackensack University Medical Center, about his presentation on an expanded access study of brexucabtagene autoleucel (brexu-cel) for patients with mantle cell lymphoma who were ineligible for the ZUMA-2 and ZUMA-18 studies. Additionally, Dr. Goy shares insights into the growing arsenal of therapies for patients with high-risk mantle cell lymphoma.
Andre Goy, MD: My name is Andre Goy. I'm a lymphoma expert, the Chair of the John Theurer Cancer Center at Hackensack University Medical Center, and Physician in Chief of Oncology for the Hackensack Network.
Oncology Data Advisor: Awesome. Thanks so much for taking the time to talk today.
Dr. Goy: Happy to be here.
Oncology Data Advisor: We're talking today about your study on outcomes of patients with relapsed/refractory mantle cell lymphoma treated with brexucabtagene autoleucel in ZUMA-2 and ZUMA-18. For background, would you like to tell us a little bit about brexu-cel, the ZUMA trials, as well as what an expanded access study is, which you're presenting?
Dr. Goy: Of course. Starting with mantle cell lymphoma relapse in ZUMA-2, this refers to a patient who had failed anti-CD20 chemotherapy and Bruton kinase inhibitors (BTK) inhibitors. We know that this population had a minimal survival that was numbered in months, depending on the series, from three to 12 months. This is obviously an unmet need.
Then came the first chimeric antigen receptor (CAR) T-cell approved anti-CD19 therapy, brexu-cel, based on the ZUMA-2 data, which was then only patients with triple failures. Patients received a CAR T-cell infusion one time, and the overall response rate was 93%, with a complete response (CR) of 68%. I'll talk about the update on long-term follow-up in a minute. This was really a game changer because these patients did really well. As we learned how to manage the toxicity, that became even better.
One of the challenges was that when the study was fully enrolled in early 2019, there were a lot of patients that were excluded who could potentially benefit from CAR T-cell therapy. So, there was this expanded access trial, ZUMA 18, which was much more flexible in a way. You had to have failed one prior therapy—a BTK, rituximab, or chemotherapy. In reality, this patient population was heavily pretreated, with a median of four prior therapies, between one and 10. There were older patients too. The study had 23 patients total.
Essentially, Cohort 1 offered them CAR T until CAR T became commercially available. There was also a Cohort 2 in which the manufacturing process led to a product that was not at the cutoff of 80% viability by the FDA. It was 74% or 78%, but it was not at the cutoff. These patients were treated in separate cohorts, and they got a standard bridging therapy as done in ZUMA-2, which is BTK and steroids. But the difference in ZUMA-18, because the patients were sicker, was that they actually could get some additional therapy to control the disease.
These patients were older—69 years old versus 65—and there were almost twice as many Eastern Cooperative Oncology Group (ECOG) performance status 1 patients versus ZUMA-2. They were more heavily pretreated and these patients were sicker. In spite of this, the partial response rate was 87% and the complete response was 57%. The median overall survival hasn't been reached, and it's 58% at 24 months. This is remarkable in that setting because these patients had no options. For perspective, the only way you can cure mantle cell lymphoma is if you could do an allogeneic (allo) transplant. But if someone is very sick or older, by the time you find a donor, they're not going to be able to do that. In addition, there's a 55% risk of chronic graft-versus-host-disease (GVHD).
What we saw in ZUMA-18 is that the median duration was a bit shorter than in ZUMA-2 because of the patients were sicker, but the CR rate was still significant, as I mentioned. During this presentation today, I also gave an update on the four-year median follow-up of the ZUMA-2 trial. The three-year data was published in the Journal of Clinical Oncology earlier this year. It showed, quite remarkably, that the median overall survival of the patient who achieved the CR is close to five years. This is versus survival only in months after triple failure. I think this is the take-home message. In ZUMA-18, although they were sicker, more heavily pretreated, and older, patients still had a high response rate. It doesn't last as long as we see on ZUMA-2, which shows that you have to do this earlier in a treatment paradigm of mantle cell lymphoma. The long-term follow-up of ZUMA-2 continues to show that patients with relapsed/refractory mantle cell lymphoma should get CAR T-cell therapy as a standard of care.
Oncology Data Advisor: Amazing, thanks so much for explaining all of this. It's great to hear about the results. You touched upon this a little bit, but did any of the results stand out as particularly significant in comparison with the previous trial?
Dr. Goy: What was significant was the fact that we had saw a response in patients who would not have qualified for ZUMA-2, which is why they were waiting. They had more disease, were more heavily pretreated, and were sicker. In spite of this, grade 3 cytokine release syndrome (CRS) was only 4%, because by then we had learned how to be proactive and preemptive in terms of managing the CRS and neurotoxicity. We almost would've expected the neurotoxicity to be worse in that older population, but it was actually manageable.
One of the questions that comes up is that what happened with the very high–risk patient, such as patients with mutation or deletion of 17p. We don't have that data, because this extended access was mostly designed for convenience of patients. We don't have this data, but we have data in ZUMA-2. And now with real-world data presented at this conference this morning, actually, in the same session, it really doesn't impact complete response rates and outcomes. For reasons that are poorly understood, there might have been more CRS and neurotoxicity, and maybe lower survival, but more cytopenias and potentially more infection for a mechanism that is still poorly understood.
Oncology Data Advisor: Thanks for explaining that data. So, what do these results mean for the continued use of brexu-cel in the relapsed/refractory mantle cell lymphoma setting?
Dr. Goy: The field of mantle cell lymphoma is expanding with more BTK inhibitors and combinations. With the third-generation non-covalent BTK, pirtobrutinib, the median duration of CR in mantle cell is still not very long; it's about 10 months. In chronic lymphocytic leukemia (CLL), the data is a little bit more impressive in durability, but there are a lot of other compound bispecifics that will have a role. We have BCL-2 inhibitors, such as venetoclax, which is used a lot in that setting. When you start to do a triplet, you can have some potential durable response, but still, no one is cured.
In this setting, patients will have early relapse, progression of disease within 24 months (POD24), for example, or patients who have high-risk disease. The high-risk disease is well beyond the Mantle Cell Lymphoma International Prognostic Index (MIPI) score and Ki-67, shown in next-generation sequencing (NGS) at baseline in terms of relapse. At baseline, 20% to 30% of patients have high-risk features—multiple mutations, TP53, deletion(17p), complex karyotype, just to name a few. These patients traditionally do very poorly with chemotherapy. There are studies that will address this. In this high-risk population, CAR T consolidation earlier would be better.
This is parallel to ZUMA-12, which was looking at high-grade lymphomas in high-risk patients who didn't achieve a CR after two cycles of R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone). They got CAR T on ZUMA-12, and at four years, the PFS was 86%. I just had a conversation with colleagues today about how we identify ahead of time who's going to be on this long-term curve. That's what we want to do. We know there are factors that are related to the patient—comorbidity, age, and all that inflammatory milieu. We know that some data in large lymphoma would apply in mantle cell if you have a better T-cell profile, particularly bendamustine. Being away from bendamustine is important if you have a better ALMC-1 ratio, which is reflection of immunosuppressive status.
Then you have a product, which when you manufacture it, doesn't have too much T-cell differentiation. It still has life cells that can expand better. Once you do the journey of the CAR T here, once you look at the patients who have been infused, what matters is the peak and the area under the curve. That's really what conditions the outcomes of patient with mantle cell. You could imagine in the future that we could monitor this more carefully and maybe adjust for the patients who are not responding enough because it really has an impact on the outcome. Could you combine with something to try to boost this immune response? Cell-free DNA at Day 28 is very important, and then obviously, immune reconstitution post–CAR T in the microbiome is barely scratching the surface. All of this is an example of areas around the journey of a CAR T patient that have active research to try to see on how we can raise the bar and make it better.
Oncology Data Advisor: That's all great to know. Anything else you'd like to mention about the study?
Dr. Goy: The study was an expanded access, and that was a lot of effort because this is a population that in general, when we do drug development, when we see something that has a promising or game-changing activity, we should have this expanded access because it allows patients to have access to a therapy that they will never get. Otherwise, they have to wait until it's approved because they will never qualify, or they won't be able to wait. I think that was a great effort, and the good thing is that you also saw that in this high-risk population you still have a very good outcome with 58% survival at 24 months.
Oncology Data Advisor: That's very impressive. Well, thank you so much for stepping by to talk about this today. It was wonderful to hear about the results.
Dr. Goy: Pleasure.
About Dr. Goy
Andre Goy, MD, is the Chairman and Chief Physician Officer of John Theurer Cancer Center at Hackensack University Medical Center in Hackensack, New Jersey. He is also the Lymphoma Division Chief of John Theurer Cancer Center and Physician in Chief of Hackensack Meridian Health Oncology Care Transformation Services. Dr. Goy specializes in lymphoma care and directs New Jersey's largest lymphoma treatment research program. He was the lead investigator in the development of several FDA-approved drugs—bortezomib, lenalidomide, and ibrutinib—for mantle cell lymphoma. Currently, his research focuses on lymphoma biomarkers, novel anticancer agents and drug combinations, and non-chemotherapy options for mantle cell lymphoma.
For More Information
Goy A, Jacobson CA, Flinn IW, et al (2023). Outcomes of patients with relapsed/refractory mantle cell lymphoma (R/R MCL) treated with brexucabtagene autoleucel (brexu-cel) in ZUMA-1 and ZUMA-18, an expanded access study. Presented at: 2023 American Society of Hematology Annual Meeting. Abstract 106. Available at: https://ash.confex.com/ash/2023/webprogram/Paper174273.html
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.