KTE-C19 Induces Complete Remissions in Phase II Lymphoma Study

Jeff Wiezorek, MD

Treatment with KTE-C19 demonstrated an objective response rate (ORR) of 79% and a complete remission (CR) rate of 52% for patients with aggressive, chemorefractory non-Hodgkin's lymphoma (NHL), according to interim findings from the multicenter phase II ZUMA-1 study released by the company developing the anti-CD19 chimeric antigen receptor (CAR)-positive T cell therapy, Kite Pharma.

The study included 51 patients with diffuse large B-cell lymphoma (DLBCL) and 11 with either transformed follicular lymphoma (TFL) or primary mediastinal B-cell lymphoma (PMBCL). For those with DLBCL, the ORR with KTE-C19 was 76%, with a CR rate of 47%. In those with TFL/PMBCL, the ORR was 91% and the CR rate was 73%.

Across the full study (n = 62), grade ≥3 cytokine release syndrome (CRS) was experienced by 18% of patients, and 34% experienced grade ≥3 neurological toxicity. There were 2 patient deaths related to KTE-C19-associated adverse events, specifically from hemophagocytic lymphohistiocytosis and cardiac arrest in a patient with CRS.

"ZUMA-1 is the largest CAR-T study reported in NHL," Jeff Wiezorek, MD, senior vice president of Clinical Development at Kite Pharma, said in a statement. "We were able to manufacture KTE-C19 for 99% of patients enrolled in the study, and successfully handle the study logistics and adverse event management at over 20 sites, most of which had no prior experience in CAR-T therapy."

Prior to receiving KTE-C19, patients were treated with a conditioning regimen of fludarabine and cyclophosphamide. KTE-C19 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.

Key inclusion criteria for the study included stable disease of less than 12 months, progressive disease as best response to most recent treatment, or disease progression or recurrence ≤12 months following autologous stem cell transplantation. In order to be eligible for the study, patients also must have received prior therapy with an anti-CD20 antibody and an anthracycline-containing regimen.

Overall, 39% of patients with DLBCL treated with KTE-C19 experienced a response for at least 3 months and 33% had a CR for at least 3 months. For those with PMBCL/TFL, the 3-month ORR and CR rates were both 64%. In the combined analysis, the 3-month ORR was 44% and the CR was 39%. Data are still pending for response duration beyond the 3 month mark.

The most common grade ≥3 adverse events with KTE-C19 included neutropenia (66%), anemia (40%), febrile neutropenia (29%), thrombocytopenia (29%), and encephalopathy (26%). Full results from the study are being prepared for future presentation at an upcoming medical meeting, according to Kite Pharma.

In the phase I portion of the ZUMA-1 trial, 7 patients with DLBCL were treated with KTE-C19. In this part of the study, the ORR was 71% and the CR rate was 57%. The 3, 6, and 9 month CR and ORR rates were each 43%, suggesting the response rate at 3 months may remain unchanged at future analyses.

Kite Pharma made comparisons between the ZUMA-1 results and the multicohort SCHOLAR-1 study, which combined findings from 2 phase III studies and 2 observational cohorts to provide a benchmark for studies into DLBCL. Overall, the SCHOLAR-1 study included 861 patients with DLBCL, of which 597 had refractory disease. Response rates ranged from 19% to 36% in the study, and CRs ranged from 2% to 18%, with a median around 8%.

"ZUMA-1 enrolled patients with chemorefractory aggressive NHL, a disease that is very difficult to treat," added Wiezorek. "The combined CR rate of 39% at 3 months is very exciting as it represents nearly a 5-fold increase from the CR rate of 8% seen in the SCHOLAR-1 study in a similar patient population."

KTE-C19 has received a breakthrough therapy designation from the FDA as a potential treatment for DLBCL, TFL, and PMBCL. In July 2016, when the study completed enrollment, the company announced plans to submit a biologics license application (BLA) to the FDA for approval of KTE-C19 in DLBCL before the end of the year, based on the phase II ZUMA-1 results. This application would be based on an analysis of the first 50 patients enrolled in the trial.

A number of other studies continue to assess KTE-C19 for patients with hematologic malignancies. The phase II ZUMA-2 study is assessing the CAR T-cell therapy in mantle cell lymphoma (NCT02601313). Additionally, the phase I/II ZUMA-3 and -4 studies are assessing KTE-C19 for patients with relapsed/refractory acute lymphocytic leukemia (NCT02614066, NCT02625480).