Updated Results From ZUMA-1 Show “Promising” Response Rates With CAR T-Cell Therapy in Relapsed/Refractory NHL

Treatment with the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel led to a high objective response rate (ORR) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to updated results of the phase I/II ZUMA-1 trial presented at the 2017 ASCO Annual Meeting. Frederick Locke, MD, from the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center and Research Institute in Tampa, Florida, shared the new data, which expand on interim data initially reported at the 2016 ASH Annual Meeting.

“One infusion of axicabtagene ciloleucel led to responses in more than 80 percent of patients and complete responses (CRs) in more than 50 percent of patients,” Dr. Locke told ASH Clinical News. “This compares favorably to the historical control data from the SCHOLAR-1 meta-analysis, which showed that, with standard of care in the same group of patients, less than one out of four patients [had] a response, and less than one out of 10 [had] a CR.”

The ZUMA-1 trial enrolled 111 patients (median age = 58 years; range = 23-76 years) with previously treated diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, or transformed follicular lymphoma from 22 institutions. Participants were required to have an Eastern Cooperative Oncology Group score of 0-1 and refractory disease.

Sixty-nine percent of patients received at least three prior lines of therapy. Most (79%) were refractory to chemotherapy and had not received autologous hematopoietic cell transplantation (AHCT). The remaining 21 percent had received AHCT but relapsed within 12 months.

“These truly were patients without any standard-of-care options,” said Dr. Locke. “More than 50 percent not only didn’t respond to their last line of chemotherapy, but they didn’t respond to their last two consecutive lines of chemotherapy.”

CAR T cells were manufactured successfully in 99 percent of patients, with an average turnaround time from apheresis to the clinical site of 17 days. As of the data cutoff date (January 27, 2017), 101 patients (91%) had received axicabtagene ciloleucel 2×106 cells/kg, following conditioning with low-dose cytarabine and fludarabine. Ten patients did not receive treatment for the following reasons: serious adverse events (AEs; n=7), no measurable disease (n=2), or product unavailability (n=1).

After a median follow-up of 8.7 months (range not provided), the ORR (primary endpoint) was 82 percent, including a CR rate of 54 percent.

As of data cutoff, 44 percent of patients maintained their response, including 39 percent of those who achieved CR, the authors noted. The median duration of response was 8.1 months (range not provided) and was not reached for patients who achieved CR. The median overall survival (OS) also was not reached during study follow-up, and the 6-month OS rate was 80 percent.

Response rates were consistent across disease subgroups, the authors added. Patients with germinal center B-cell (GCB) DLBCL and activated B-cell (ABC) DLBCL had similar ORR and CR rates to the general study population:

  • GCB (n=69): 88% and 57%
  • ABC (n=69): 76% and 59%

Also, levels of CD19 expression did not appear to influence response rates to this CD19-directed therapy: Of the 82 patients who were evaluable for CD19 expression (measured via immunochemistry) at the time of follow-up, 90 percent were CD19 positive; rates of ORR and CR were similar between CD19-positive and CD19-negative patients (85% and 57% vs. 75% and 50%, respectively).

The most common grade ≥3 treatment-related AEs included neutropenia (66%), leukopenia (44%), anemia (43%), febrile neutropenia (31%), thrombocytopenia, (24%), and encephalopathy (21%).

Cytokine release syndrome (CRS) and neurologic toxicities were the AEs of most concern, given reports from other trials of CAR T-cell therapies. (Earlier this year, Kite Pharmaceuticals, the manufacturer of KTE-C19, reported that one patient enrolled in the safety expansion phase of ZUMA-1 died from cerebral edema, marking the first death from cerebral edema recorded in the KTE-C19 clinical trials program.) Thirteen percent and 28 percent of patients experienced severe, grade ≥3 CRS and neurologic events, respectively, but all of the events were resolved except for one grade 1 memory impairment.

In the subset of 70 patients who experienced CRS or neurologic events, 43 required treatment with tocilizumab and 27 required treatment with tocilizumab and steroids, but these treatments did not decrease the efficacy of axicabtagene ciloleucel (ORR = 84% and 78%, respectively). “These therapies kind of ‘turn off’ immune responses, but we found that patients who needed them had very similar response rates [to those who did not],” Dr. Locke said.

Three patients died during study follow-up, but, he added, “considering that these patients are without any other treatment options, we think that the risk-reward benefit is favorable.”

The study’s findings are limited by the short duration of follow-up and the single-arm design. Based on results from this trial, the manufacturers of axicabtagene ciloleucel submitted a biologics license application to the U.S. Food and Drug Administration for the treatment of patients with aggressive NHL who are ineligible for AHCT.

Dr. Locke reports research funding from Kite Pharma.


Locke FL, Neelapu SS, Bartlett NL, et al. Clinical and biologic covariates of outcomes in ZUMA-1: a pivotal trial of axicabtagene ciloleucel (axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (r-NHL). Abstract #7512. Presented at the 2017 ASCO Annual Meeting, June 5, 2017; Chicago, Illinois.