Axicabtagene Ciloleucel Shows High CR Rates in Primary Analysis of ZUMA-1 Study

Frederick L. Locke, MD

Treatment with axicabtagene ciloleucel (KTE-C19) demonstrated an objective response rate (ORR) of 82% and a complete response (CR) rate of 54% for patients with aggressive non-Hodgkin lymphoma, according to the primary analysis of the ZUMA-1 trial announced by Kite Pharma, the company developing the CAR T-cell therapy.

Responses were seen across subgroups in the study, including those with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and transformed follicular lymphoma (TFL). In those with DLBCL (n = 77), the ORR was 82% and the CR rate was 49%. In the PMBCL/TFL group (n = 24), the ORR was 83% and the CR rate was 71%.

"Several patients we treated at Moffitt Cancer Center experienced a rapid and durable complete response with this first-of-its kind therapy," co-lead investigator Frederick L. Locke, MD, director of research for the Immune Cell Therapy Program at Moffitt Cancer Center, said in a statement. "The ZUMA-1 study results suggest that axicabtagene ciloleucel could become a new standard of care for patients with refractory aggressive lymphoma."

In the trial, patients were enrolled into 2 cohorts consisting of those with DLBCL (cohort 1) and those with PMBCL/TFL (cohort 2). All patients had chemorefractory disease, with roughly 80% refractory to their last line of chemotherapy, and the remainder relapsing within 12 months of autologous transplant. Patients had received a median of 3 prior therapies.

Prior to axicabtagene ciloleucel, a conditioning regimen of fludarabine and cyclophosphamide was administered. Axicabtagene ciloleucel was administered as a single infusion of modified autologous T cells at a target dose of 2 x 10⁶ CAR-positive T cells/kg.

The primary endpoint of the phase II study was ORR, which was significantly satisfied across the full study (P <.0001). After 6 months, 41% of patients continued to respond, with a CR rate of 36% and a partial response (PR) rate of 5%. There was one incidence of a PR transitioning to a CR after 9 months, suggesting longer follow-up could alter these numbers.

The median follow-up for the primary analysis was 8.7 months, with most patients having data available for 6 months. There were 4 patients who experienced a CR but did not have assessment data available for 6 months. For the primary analysis, these individuals were classified as non-responders, suggesting the response rates could be higher.

The ORR at 6 months for those with DLBCL was 36%, which included a CR rate of 31%. In the TFL/PMBCL group, the 6 month ORR rate was 54%, with a CR rate of 50%. Median overall survival was not yet reached.

In the absence of a comparator arm, the researchers contrasted the findings with a similar population of patients from the SCHOLAR-1 study, which combined findings from 2 phase III studies and 2 observational cohorts to provide a benchmark for studies into DLBCL. In this study, which included 597 patients with refractory DLBCL, the response rates ranged from 19% to 36%, and CRs ranged from 2% to 18%, with a median around 8%. The median overall survival was 6.6 months.

"We know as clinicians that patients with aggressive lymphoma who do not respond to their previous treatments have a very poor prognosis. In fact, we know from the SCHOLAR-1 study, these patients have only an 8% chance of achieving a complete response with current therapies," said Locke.

Data from 93 patients were available for the interim analysis from the ZUMA-1 trial, whereas the primary assessment contained data for 101 patients. With more patients assessed, the rate of CRS declined from 18% at the interim assessment to 13% for the primary analysis. Additionally, neurologic events dropped from 34% in the interim analysis to 28% in the primary assessment. There continued to be no cases of cerebral edema.

"These results with axicabtagene ciloleucel are exceptional and suggest that more than a third of patients with refractory aggressive NHL could potentially be cured after a single infusion of axicabtagene ciloleucel," said Jeff Wiezorek, MD, senior vice president of Clinical Development at Kite Pharma, said in as statement.

Kite Pharma initiated a rolling submission of data to the FDA for a biologics license application in December 2016, which is permitted as part of a breakthrough therapy designation received by axicabtagene ciloleucel in December 2015. The company is seeking approval for patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma who are ineligible for autologous stem cell transplant. Kite expects to complete this submission before the end of March.

Full data from the primary analysis of the ZUMA-1 trial will be presented at the 2017 AACR Annual Meeting.

The most common grade ≥3 adverse events (AEs) were anemia (43%), neutropenia (39%), decreased neutrophil count (32%), febrile neutropenia (31%), decreased white blood cell count (29%), thrombocytopenia (24%), encephalopathy (21%), and decreased lymphocyte count (20%). There were 3 fatal events in the study, 2 of which were deemed related to axicabtagene ciloleucel: hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of cytokine release syndrome (CRS). The third death was from pulmonary embolism.