ZUMA-1 at One Year: Durable Responses to Axicabtagene Ciloleucel in Patients With Aggressive NHL

In October 2017, axicabtagene ciloleucel became the second chimeric antigen receptor (CAR) T-cell therapy approved by the U.S. Food and Drug Administration, and the first gene therapy approved to treat patients with non-Hodgkin lymphoma (NHL), based on results of the phase II ZUMA-1 trial. At the 2017 ASH Annual Meeting, researchers shared an update from the trial, which showed that patients are maintaining the impressive response rates at one year.

“Long-term follow-up of ZUMA-1 confirms that these responses can be durable and the ongoing responses at 24 months suggest that late relapses are uncommon,” said lead author Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, during his presentation of the results. “With existing therapy, the median survival for people with this disease is only six months. Here, we see more than half of patients – 59 percent – are still alive over a year after treatment.”

The ZUMA-1 trial enrolled 108 adult patients (median age = 58 years; range = 23-76 years) with refractory diffuse large B-cell lymphoma, transformed follicular lymphoma, and primary mediastinal large B-cell lymphoma who had received a prior anti-CD20 antibody and an anthracycline-containing regimen. Patients received axicabtagene ciloleucel 2×106 cells/kg, following conditioning with low-dose cytarabine and fludarabine.

By August 11, 2017 (data cutoff), no patients were lost to follow-up, and all patients who are alive are continuing follow-up.

In the pivotal data from ZUMA-1, patients achieved an objective response rate (ORR) of 82 percent and a complete response (CR) rate of 54 percent after a single infusion of axicabtagene ciloleucel. In this updated analysis of phase I and II of ZUMA-1, the ORR remained 82 percent, and the CR rate rose to 58 percent after a median follow-up of 15.4 months (range not provided).

Sixty patients had either a partial response (PR; n=35) or stable disease (SD; n=25); at the first tumor assessment (1 month post-infusion), 23 patients with either PR or SD subsequently achieved CR up to 15 months, without additional therapy. The median time to conversion from PR to CR was 64 days (range = 49-424 days).

Median duration of CR had not been reached by data cutoff, with three of seven patients (43%) in ongoing CR at 24 months. Median progression-free survival was 5.8 months (range = 3.3 months – not reached), while the median overall survival (OS) was not reached (range = 12.0 months – not reached).

“Patients who are in remission at six months tend to stay in remission,” Dr. Neelapu said, adding that, while the median OS was not reached, “there is a plateauing of the OS curve at the 16-month timepoint.”

The investigators also reviewed baseline and post-progression biopsies for in 12 evaluable patients, shedding some light on why certain patients’ disease fails to respond to treatment. About one-third of patients experienced CD19 antigen loss at the time of disease progression, and 80 percent of patients evaluable for PD-L1 at time of disease progression showed PD-L1–positive disease (see TABLE). “Loss of CD19 and gain of PD-L1 expression in tumors are identified as possible mechanisms of resistance following axicabtagene ciloleucel treatment,” the authors noted.

The safety profile was consistent with previously reported studies of axicabtagene ciloleucel, Dr. Neelapu added. In earlier analysis of ZUMA-1, four patients died within two months after CAR T-cell infusion, two of which were deemed related to study treatment and two attributable to unrelated adverse events (AEs). In this longer-term follow-up, no new treatment-related deaths were observed.

Nearly all patients experienced at least one grade ≥3 AE (n=105; 97%), and nearly half experienced a grade ≥3 serious AE (n=50; 46%). “Since the primary analysis with six months and longer follow-up, there have been no new treatment-related cytokine release syndrome [CRS; an AE commonly associated with CAR T-cell therapy], neurologic event, or grade 5 AEs,” Dr. Neelapu said.

In the pivotal portion of ZUMA-1, the most common AEs were CRS, neurologic toxicities, neutropenia, neutropenia, anemia, and thrombocytopenia. Ten patients in the longer-term analysis experienced a late-onset serious AE, including pneumonia, influenza infection, and lung infection.

The findings of this study are limited by the lack of a comparator arm, and Dr. Neelapu noted that a randomized trial comparing the efficacy of axicabtagene ciloleucel with secondline standard of care (including autologous hematopoietic cell transplantation for relapse after firstline therapy) is planned in patients with aggressive B-cell NHL. Other follow-up studies are identifying possible approaches to overcoming antigen loss and the development of PD-L1 in CAR T-cell–treated patients.

The authors report financial relationships with Kite Pharma, Inc. (now Gilead Sciences), which also provided funding for this study.


Neelapu SS, Locke FL, Bartlett NL, et al. Long-term follow-up ZUMA-1: a pivotal trial of axicabtagene ciloleucel (Axi-Cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). Abstract #578. Presented at the 2017 American Society of Hematology Annual Meeting, December 11, 2017; Atlanta, GA.