ZUMA-5 in R/R Follicular Lymphoma

Ian Flinn, MD, PhD: We’re going to change gears and talk a little about CAR [chimeric antigen receptor] T-cell therapies. We’ve now seen CAR T cells approved for large B-cell lymphoma and mantle cell lymphoma. There are a number of CAR T-cell therapies under investigation in follicular lymphoma. Caron, you presented data at ASH [American Society of Hematology Annual Meeting] on axi-cel [axicabtagene ciloleucel] in patients with follicular lymphoma—the ZUMA-5 study. Can you talk through some of that trial? Why is it being conducted? What results are being seen, and where do you see that therapy fitting in for follicular lymphoma?

Caron A. Jacobson, MD, MMSc: This is a phase 2 open-label study of axi-cel [axicabtagene ciloleucel], which is an anti-CD28/CD19 CAR T-cell therapy that’s been approved for adults with relapsed/refractory large B-cell lymphoma. It leads to long-term remissions in about 40% of those patients. This has really become definitive and revolutionary therapy for patients who didn’t have other curative or successful treatment options. There’s no reason to think you can’t apply it to other CD19-positive diseases.

As we started discussing at the beginning of our discussion, follicular lymphoma is an incurable disease. While there are a lot of unmet needs in follicular lymphoma, 1 of them is the elusive cure. The hope is that by using immunologic therapies like allotransplant, although maybe a little safer than allotransplant, you could change the natural history of this disease.

The ZUMA-2 study looked at patients in the third-line setting. We spoke about PI3 kinase inhibitors leading to about an 11-month progression-free survival in that setting. We treated patients with a single infusion of axi-cel [axicabtagene ciloleucel].

The trial included both follicular lymphoma and marginal zone lymphoma patients, but when you look just at the follicular lymphoma cohort, the response rate was 94% with an 80% CR [complete response] rate. That’s probably 1 of the highest CR rates we’ve seen in this multiple relapsed/refractory setting. What’s more important is, of course, not the CR rate but the durability of response. The median follow-up for duration of response was 17.5 months. Looking specifically at 12 months, 72% of patients with follicular lymphoma remained responsive to treatment.

Of course, we need longer follow-up data in a disease like this to understand if this is a therapy that can equally change the natural history of this disease and transform outcomes for these patients in later lines of therapy, but the early results are very encouraging. These responses were seen across all risk groups, including the POD24 [progression of disease within 24 months] patients.

One of the most notable things about it is that we talked about CRS [cytokine-release syndrome] and neurological toxicity when we talked about the CD20 bispecifics. We know what the CD28 CAR T-cell therapies can do in large B-cell lymphoma, in terms of rates of high-grade cytokine release syndrome and neurological toxicity, but this had a more favorable safety profile than what we saw in large B-cell lymphoma.

The rates of grade 3 and higher CRS, which is ICU [intensive care unit]–level cytokine release syndrome, were only 6% in the follicular lymphoma cohort. The rates of grade 3 and higher neurological toxicity were about half of what we see in large B-cell lymphoma, about 15%.

From personal experience, these patients had a much easier course. The fevers started later and didn’t last as long, and many of these patients had no neurological toxicity. Overall, I’m very optimistic about where CAR T-cell therapies are going to fit in this landscape, but I may be a little biased.

Ian Flinn, MD, PhD: You have to have the courage of your convictions. I want to just stick with you for a second. Is there a biological reason why there’s less severe adverse events in follicular lymphoma compared to large B-cell lymphoma, or are we just smarter and better at giving these—intervening earlier and getting better at administering the therapy?

Caron A. Jacobson, MD, MMSc: There’s absolutely a biological reason. We know that high-grade CRS and neurological toxicity is increased in patients who have high pretreatment inflammatory markers. In our patients with follicular lymphoma, the pretreatment CRP [C-reactive protein] and ferritin and IL-6 levels are much lower than what they are in large B-cell lymphoma. The testament to that being disease driven is the fact that in large B-cell lymphoma, with axi-cel [axicabtagene ciloleucel] 95% of patients have grade 1 CRS with a fever. In follicular lymphoma, only 77% had grade 1 CRS. You can’t prevent the onset of CRS. We’re not good at doing that yet. If we were, we’d be better at managing this in large B-cell lymphoma. That speaks to the fact that with these patients, the disease interfaces with inflammatory response in a much less significant way than large B-cell lymphoma. Whether that’s microenvironment or the disease itself, I don’t know.

Transcript Edited for Clarity