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WASHINGTON -- The autologous anti-CD19 chimeric antigen receptor (CAR) T-cell, axicabtagene ciloleucel demonstrated significant clinical benefit, and an acceptable safety profile in patients with refractory aggressive non-Hodgkin lymphoma (NHL), researchers reported here.

Primary results from the ZUMA-1 phase II trial demonstrated an objective response rate (ORR) of 82% (P<0.0001) and a complete response (CR) of 54% in 101 patients treated with axicabtagene ciloleucel (axi-cel), according to Frederick L. Locke, MD, of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla., and colleagues.

This was consistent across key covariates including disease subtype, refractory status, stage, and International Prognostic Index (IPI) score, he noted in a presentation at the American Association for Cancer Research (AACR) meeting.

The median duration of response (DOR) was 8.2 months overall, and at 6 months, 80% of patients were still alive, triggering the primary analysis, Locke said at a median follow-up of 8.7 months, 44% of patients had an ongoing response and 39% were in CR.

Overall, cases of cytokine release syndrome (CRS) and neurological events tended to be reversible and rates for each decreased over the course of the study.

"Axi-cel significantly improved ORR in patients with refractory aggressive NHL," Locke stated. "The CR rate was seven-fold higher compared to historical controls, and nearly half the patients have an ongoing response. Axi-cel demonstrated significant clinical benefit with a manageable safety profile in patients lacking curative treatment options."

"ZUMA-1 is a major step forward," said AACR session discussant Renier Brentjens, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, noting that most previous studies have been phase I trials.

The living drug requires only a single infusion and has universal application since antigen recognition is HLA-independent, Brentjens pointed out. In addition, CAR T-cell therapy is active in both CD4 and CD8 T cells, rapidly generating tumor-specific T cells with minimal risk of autoimmunity or graft versus host disease (GvHD).

Refractory and aggressive NHL is the most common hematological malignancy in the U.S., Locke said. Currently, there is no accepted standard of care for patients with refractory disease who have not responded to frontline or salvage therapy, or who have relapsed after autologous transplant.

Previously, , a meta-analysis of 635 patients with relapsed-refractory diffuse large B cell lymphoma, showed that treatment with third- or fourth-line therapies also carried a dismal prognosis with a reported ORR of 26%, CR of 8%, and a median OS of about 6 months.

In their of axi-cel (formerly KTE-C19) in 62 patients with refractory aggressive NHL, Locke's group reported an ORR of 79% and a CR of 52%. Again, rates were nearly six times higher than historical controls in SCHOLAR-1.

"There is a significant unmet need," said Locke, pointing out that axi-cel CAR T-cell therapy has a CD37/CD28-based signaling that recognizes CD-19-expressing cells and eliminates them.

At the ZUMA-1 data cutoff on Jan. 27, 2017, 111 patients from 22 institutions were enrolled with aggressive NHL: diffuse large B cell lymphoma (DLBCL); primary mediastinal B cell lymphoma (PMBCL); or transformed follicular lymphoma (TFL) with an ECOG performance status of 0-1. Refractory disease was defined as either progressive or stable disease as best response to last prior therapy, or relapse within 12 months of autologous stem cell transplant.

Median patient age was 58, 67% were male, and 85% had stage III/IV disease. In 47% of the study participants, IPI score was 3-4 and 77% were refractory to a second line of therapy, while 21% had relapsed in the year following autologous stem cell transplant.

Axi-cel was successfully manufactured in 110/111 (99%) patients with an average turnaround time of 17 days from apheresis to the clinical site. Peak and cumulative CAR T levels post-axi-cel were associated with durable responses.

A total of 101 patients (91%) received a target dose of 2 × 106 anti-CD19 CAR T cells/kg and were put into a modified intent-to-treat (mITT) group after low-dose conditioning with cyclophosphamide (cy) 500 mg/m2 plus fludarabine (flu) 30 mg/m2 x 3 days.

The primary endpoint for the analysis was the ORR in the first 92 patients dosed in the combined DLBCL, PMBCL, and TFL population. This group was divided into two cohorts:

• Cohort 1: 72 patients with refractory DLBCL
• Cohort 2: 20 patients with refractory PMBCL or TFL

The most common treatment-emergent adverse effects of grade 3 or higher included neutropenia (66%), leukopenia (44%), anemia (43%), febrile neutropenia (31%), and encephalopathy (21%). Cytokine release syndrome (CRS) of grade 3 or higher occurred in 13% of patients, but all resolved with the exception of one case of hemophagocytic lymphohistiocytosis (HLH) and one case of cardiac arrest.

Neurologic events occurred in 28% of patients and all resolved except for one case of grade 1 memory impairment. Neurological symptoms such as delirium, global encephalopathy, aphasia, seizure, and cerebral edema, are reversible at current CAR-T cell dose levels, Brentjens pointed out, noting these can occur independent of CRS.

There were also three grade 5 adverse events, representing 3% of patients. In 43% of patients who received tocilizumab (Actemra) and 27% who received steroids, there were no cases of cerebral edema and no new cases of grade 5 adverse effects.

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