CAR T Therapy and Durable Responses in MCL - Episode 2

ZUMA-2 Trial and Implications For CAR T in MCL

Frederick Locke, MD, discusses the ZUMA-2 trial, including the study design, results, and practical implications for CAR T in patients with mantle cell lymphoma.

Frederick Locke, MD: The ZUMA-2 clinical trial is testing CAR [chimeric antigen receptor] T-cell therapy for patients with refractory mantle cell lymphoma. ZUMA-2 tests a CAR T-cell therapy called brexucabtagene autoleucel, which is a CD19-directed CAR T-cell therapy that contains a CD28 costimulatory domain. It is the exact same construct as in axicabtagene ciloleucel, but the manufacturing process is different, where the T-cells are selected out prior to manufacturing.

Brexucabtagene autoleucel was tested in patients with relapsed or refractory mantle cell lymphoma [MCL] who had 1 to 5 prior lines of therapy. Patients had leukapheresis, where their cells were collected and brexucabtagene-autoleucel was manufactured. During that manufacturing period, they could receive bridging therapy with dexamethasone, ibrutinib, or acalabrutinib if necessary. Once the CAR T-cells were manufactured, patients received conditioning chemotherapy with fludarabine and cyclophosphamide for 3 days and then received 2 x 106 brexucabtagene-autoleucels per kg in a single infusion.

Of course, the primary end point was objective response rate. The response rate in these highly refractory mantle cell lymphoma patients is pretty remarkable. The complete response rate was 67% when we looked at the data in the 1-year follow-up; 67% by investigator assessment. A partial response rate of 25% gives us an overall response rate of 92% with a single infusion. These are patients who previously had multiple lines of therapy. These patients had been exposed to a prior BTK inhibitor, and almost all of them were refractory to that BTK inhibitor. This is a highly refractory patient population that we’re talking about.

At a median follow-up of 17.5 months, 29 of 60 evaluable patients, or 48%, remain in an ongoing response, including 70% of those who achieved a complete response. Remarkable and durable remissions were achieved on the ZUMA-2 clinical trial. It’s also important to note that when we looked at ongoing response rate as stratified by high risk or other features generally associated with worse outcomes with mantle cell lymphoma, we did not see any statistical significance of any particular adverse prognostic subgroups. Patients who were over 65 had the same durable response rates. Patients who had blastoid variants had the same durable response rates as other patients. Patients with high Ki-67 proliferation index similarly had the same rates of durable remission. The same held true for patients with intermediate or high-risk MIPI [MCL International Prognostic Index] scores, or patients with a TP53 mutation. Even in high-risk patients, we’re seeing remarkable, durable response rates with brexucabtagene autoleucel CAR T-cell therapy.

Certainly, the therapy is not without some downsides. It can cause toxicity, as we know CAR [chimeric antigen receptor] T-cell therapy can. These are generally self-limited and reversible toxicities, with categories such as cytokine release syndrome [CRS] or neurological events. In fact, these are very similar to the rates of CRS and neurological events seen with axicabtagene ciloleucel for diffuse large B-cell lymphoma, and are generally very manageable and self-limited in these patients.

This transcript was edited for clarity.