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

Silas Inman @silasinman
Published: Tuesday, Feb 28, 2017

Dr Frederick L. Locke

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.

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.

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.

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