David Chang, MD, PhD
The first cerebral edema death in the ZUMA-1 chimeric antigen receptor (CAR) T-cell therapy trial was disclosed today by Kite Pharma on a conference call with investors announcing the company’s first quarter financial results.
The patient was participating in a safety expansion of the phase II ZUMA-1 study of the anti-CD19 CAR T-cell therapy axicabtagene ciloleucel (KTE-C19; axi-cil). The trial is evaluating axicabtagene ciloleucel for the treatment of patients with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) who are ineligible for transplant.
The company completed enrollment of 30 US patients last month. Two patients have experienced grade 3 cytokine release syndrome (CRS). The company said that 1 of those patients also experienced multiorgan failure and a neurologic event that progressed to a fatal cerebral edema that investigators determined was related to axicabtagene ciloleucel. Kite said that this patient had shown inadequate responses to both first- and second-line therapies, and had “rapidly progressive and symptomatic disease” at enrollment.
“In late April, we learned of this event in a very sick patient with explosive disease, meaning a rapidly progressive and symptomatic disease,” said Kite chief medical officer David D. Chang, MD, PhD. “This patient had shown inadequate responses to both first- and second-line therapies, and those involved in care felt that CAR T therapy was the best and only remaining option.
“The explosive nature of the patient’s lymphoma immediately prior to and up to the day of axi-cil therapy is a consideration and is being further investigated.”
Chang said that this was the first grade 5 cerebral edema event recorded in approximately 300 patients treated with axicabtagene ciloleucel. He added the patient consent form will be updated to reflect the risk for fatal cerebral edema, but all axicabtagene ciloleucel studies will continue as planned.
This is the third death attributed to axicabtagene ciloleucel treatment in ZUMA-1. The company previously disclosed fatal incidents of hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of CRS. A fourth death from pulmonary embolism was not related to treatment.
In March, Kite applied for a biologics license application (BLA) for axicabtagene ciloleucel based on preliminary results from ZUMA-1. Axicabtagene ciloleucel demonstrated an objective response rate (ORR) of 82% and a complete response (CR) rate of 54% in patients with NHL. Researchers observed responses across subgroups in the study, including patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and transformed follicular lymphoma (TFL).
It was expected at the time that the FDA would give the application priority review and make a ruling 4 months earlier than with a standard review. Kite announced at the time that it planned to launch later this year, and Kite president and CEO, Arie Belldegrun, MD, said that timeline had not changed.
“Kite is intensely focused on bringing axicabtagene ciloleucel to market in 2017,” he said.
Researchers presented updated results for ZUMA-1 at the 2017 AACR Annual Meeting. Objective response rate (ORR) recorded after a single infusion of axicabtagene ciloleucel remained 82% (P
<.0001), meeting the primary objective.
Patients with chemorefractory disease were segregated into DLBCL (n = 77) and PMBCL/TFL (n = 24) cohorts. Approximately 80% of patients were refractory to their last line of chemotherapy; the remainder relapsed within 12 months of autologous transplant. Patients had received a median of 3 prior therapies.
All patients underwent conditioning regimen of fludarabine and cyclophosphamide. 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.
Median follow-up was 8.7 months, with most patients available for analysis at 6 months. Four patients experienced CR but did not have assessment data available. Researchers classified these patients as nonresponders, which may mean response rates could be higher than initially reported.
Across the full duration of the study, patients with DLCBL had an ORR of 82% and a CR rate of 49%. In the PMBCL/TFL group, ORR was 83% with a CR rate of 71%.
In ongoing results, ORR was 36% in the DLBCL group with a CR of 31%. ORR rate was 67% with a CR of 63% in the PMBCL/TFL group. Median overall survival was not yet available.
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%). Researchers observed grade ≥3 CRS in 13% of patients and 28% of patients experienced neurologic events.
This is the second incidence this year of deaths due to cerebral edema among companies striving to perfect the process of developing CAR T cell therapy. In March, Juno Therapeutics discontinued the phase II ROCKET trial evaluating JCAR015 in patients with relapsed or refractory B cell acute lymphoblastic leukemia because of 2 fatal cerebral edemas.
Locke FL, Neelapu SS, Bartlett NL, et al. Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (Axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). Presented at: 2017 AACR Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT019.