Frederick L. Locke, MD
More than 80% of patients with refractory non-Hodgkin lymphoma (NHL) achieved objective responses to treatment with the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (KTE-C19), results of a pivotal phase II trial showed.1
The 82% objective response rate (ORR) in 101 patients included complete responses (CRs) in 54% of patients. In general, responses were durable, persisting for a median 8.2 months, according to findings for the ZUMA-1 trial reported at the 2017 AACR Annual Meeting.
The patients had a median progression-free survival of 5.9 months. Among patients who achieved objective responses, the median overall survival (OS) had yet to be reached after a median follow-up of 8.7 months.
“This is the first pivotal trial of anti-CD19 CAR T-cells in refractory, aggressive non-Hodgkin lymphoma, and the results demonstrated a significant benefit for patients lacking curative options,” co-lead investigator Frederick L. Locke, MD, said in presenting the data. “The complete response rate of 54% is about 7 times higher than the historic control rate of 8% in patients with refractory non-Hodgkin lymphoma.”
The results of the ZUMA-1 study have been submitted to the FDA to support a biologics license application for axicabtagene ciloleucel as a potential treatment for transplant-ineligible patients with relapsed or refractory aggressive NHL, according to Kite Pharma. The company, which has been developing the drug under a breakthrough therapy designation, anticipates launching axicabtagene ciloleucel this year if the application is successful.
Axicabtagene ciloleucel, also identified as Axi-cel, is developed by engineering the patient's T cells to express a CAR that targets the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias.
Locke said patients in the ZUMA-1 trial experienced durable benefit with manageable toxicities. “Response is ongoing in 44% of responding patients,” said Locke, a medical oncologist at Moffitt Cancer Center in Tampa, Florida. “Cytokine release syndrome [CRS] and neurologic events occurred in most patients but were generally reversible.”
An analysis of potential markers for clinical benefit for the therapy showed “consistent efficacy and safety across a broad range of CD4/CD8 ratios,” said Locke, who reported biomarker lysis in a second presentation at the conference.2
Objective response was associated with higher levels of anti-CD19 CAR T-cells.
Higher levels of anti-CD19 CAR T-cells also were associated with higher-grade neurologic events, but not CRS, both of which are common effects of CAR T-cell therapy. Increased production of cytokines and chemokines was associated with grade 3+ neurologic events and CRS, said Locke.
CAR T-cell therapy has evolved, in part, in response to a substantial unmet need in refractory, aggressive NHL. Outcomes in refractory NHL remain poor, as reflected in a recent meta-analysis that showed an overall response rate of 26% and a median OS of 6.6 months.
The ZUMA-1 findings that Locke reported involved 2 cohorts of patients with aggressive, refractory NHL. One cohort comprised patients with refractory diffuse large B-cell lymphoma (DLBCL, N = 72), and the second cohort (N = 20) included patients with refractory primary mediastinal B-cell lymphoma (PMBCL) or transformed follicular lymphoma (TFL).
Eligible patients had chemotherapy-refractory disease, defined as no response to the most recent chemotherapy regimen or relapse within 12 months after stem-cell transplant. Other eligibility criteria included prior treatment with an anti-CD20 antibody, exposure to an anthracycline, and ECOG performance status of 0-1.
The trial had a primary endpoint of ORR. Key secondary endpoints included duration of response, OS, safety, and levels of CAR T cells and cytokines.
Investigators at 22 sites enrolled 111 patients. No bridging therapy was allowed prior to conditioning, which consisted of cyclophosphamide 500 mg/m2
plus fludarabine 30 mg/m2
, administered for 3 days. Subsequently, 101 patients received axicabtagene ciloleucel, administered once at a dose of 2 x 106
The trial had a CAR T-cell manufacturing success rate of 99%. The turnaround time from apheresis to delivery to the clinical site averaged 17 days, said Locke.
The primary analysis included 92 patients, and the intention-to-treat analysis included all 101 patients. The ITT population consisted of 77 patients with DLBCL and 24 with PMBCL/TFL. Locke said 78 patients qualified for the trial because their disease was refractory to second- or later-line therapy, and 21 had posttransplant relapse within 12 months.
The ITT analysis of the primary endpoint showed an ORR of 82% in the patients with DLBCL (CRs in 49%), 83% in the PMBCL/TFL cohort (71% CR), and 82% in all 101 patients.
“Responses to Axi-cel were consistent across all key covariates,” said Locke.