KTE-C19 Response Rates Spark FDA Submission for Aggressive Lymphomas

Frederick L. Locke, MD

Treatment with the CD19-directed CAR T-cell therapy KTE-C19 showed a complete remission (CR) rate of 73% for patients with aggressive, chemorefractory primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL), according to findings from the multicenter phase II ZUMA-1 study presented at the 2016 ASH Annual Meeting.

The objective response rate (ORR) with the CAR T-cell therapy was 91% and all CRs occurred within the first month of treatment. After 3 months, both the CR and ORR rates were 64%. Cytokine release syndrome (CRS) occurred in 91% of patients, which was primarily low-grade; however, there was 1 death related to cardiac arrest in the setting of CRS.

Findings for those with PMBCL/TFL along with a cohort of patients with diffuse large B-cell lymphoma (DLBCL) are being submitted on a rolling basis to the FDA for potential approval of KTE-C19, according to the developer of the drug, Kite Pharma. The biologics license application, which is expected to be fully submitted by the end of the first quarter of 2017, will be for patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who are ineligible for autologous stem cell transplant.

"ZUMA-1 is the first multicenter CD19 CAR study in refractory DLBCL, PMBCL, and TFL," commented lead investigator Frederick L. Locke, MD, Department of Blood and Marrow Transplantation, Moffitt Cancer Center. "The trial is ongoing at 22 cites and there has been a 100% manufacturing success rate."

The phase II ZUMA-1 study contained 2 treatment cohorts. The first enrolled 72 patients with diffuse large B-cell lymphoma (DLBCL) and the second included 20 patients with PMBCL/TFL. The prespecified interim analysis for the trial was triggered by 50 patients enrolling in cohort 1. At this point, 11 patients were assessable in cohort 2, which were presented by Locke.

At enrollment, patients underwent leukapheresis for KTE-C19 manufacturing. Beginning 5 days prior to KTE-C19 infusion, all patients were treated with a conditioning regimen of fludarabine (30 mg/m²) and cyclophosphamide (500 mg/m²). 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 CAR-modified T-cells were manufactured in a 6- to 8-day process that had a 100% success rate in the multicenter trial that included 22 sites. The total time from leukapheresis to infusion was 17.5 days.

"A turnaround time of 17 days is pretty remarkable. These are patients with pretty active disease, so getting cells back in less than 3 weeks is pretty fantastic," said Locke.

Upon infusion, CAR T cells rapidly expanded within the first 7 to 14 days. This expansion was evidenced by upregulation of key cytokines and chemokines, namely IL-15, IL-6, CRP, Granzyme 8, IP-10, and IL-10. The response kinetics leveled off after 30 days, Locke noted.

Grade ≥3 adverse events (AEs) were experienced by 91% of patients in cohort 2 of the trial, and 73% of participants had serious AEs. The single episode of cardiac arrest was the only grade 5 event.

CRS specific symptoms, which were all grade 1/2, included pyrexia (82%), hypotension (27%), tachycardia (27%), and other events (18%). To treat CRS, 45% of patients received tocilizumab and 36% were treated with steroids, which resolved CRS for 9 of 10 patients.

Neurologic events were experienced by 64% of patients, and the grade 3 neurologic AE rate was 55%. The most common neurologic events were encephalopathy (36%, all grade 3), confusion state (27%), tremor (27%), aphasia (18%), and somnolence (18%). These events resolved in all patients and there were no cases of cerebral edema.

Further findings from the ZUMA-1 study are also being presented from the 2016 ASH Annual Meeting during the late-breaking abstract session for cohort 1 of the study. This arm included those with DLBCL. In results announced in September, the ORR with KTE-C19 was 76% in this cohort, with a CR rate of 47%.

Locke FL, Neelapu SS, Bartlett NL, et al. A Phase 2 Multicenter Trial of KTE-C19 (anti-CD19 CAR T Cells) in Patients With Chemorefractory Primary Mediastinal B-Cell Lymphoma (PMBCL) and Transformed Follicular Lymphoma (TFL): Interim Results From ZUMA-1. Presented at: 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 998.

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The median age of patients in cohort 2 was 57 years (range, 28-68), and 36% were ≥60 years of age. The ECOG performance status was 0 (64%) or 1 (36%) for all patients and 36% had received ≥5 prior therapies. The most common disease stage was III/IV (82%) and 45% of patients had an IPI risk of 3 or 4. Eighty-two percent of patients were refractory to their second-line therapy and 18% had relapsed on stem cell transplant (18%).