Axicabtagene Ciloleucel Approaches EU Approval for DLBCL, PMBCL

Alessandro Riva, MD

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of axicabtagene ciloleucel (axi-cel; Yescarta) as a treatment for adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) or primary mediastinal large B-cell lymphoma (PMBCL), following at least 2 lines of systemic therapy, according to Kite (Gilead), the manufacturer of the CAR T-cell therapy.

The recommendation is based on findings from the single-arm phase II ZUMA-1 trial. Results for the study presented at the 2017 AACR Annual Meeting showed that axi-cel had an objective response rate (ORR) of 82% and a complete remission (CR) rate of 54%. After 8.7 months of follow-up, 39% of patients remained in CR. The median duration of response in those with a CR was not reached at the time of the assessment (95% CI, 8.1-not estimable). The FDA label for the medication in the United States lists the ORR as 72% and the CR rate as 51% (95% CI, 41%-62%).

The European Commission will now review the CHMP recommendation and make a final decision on whether to approve axicabtagene ciloleucel for use in the European Union.

“This CHMP positive opinion is an important milestone for those patients in the European Union living with DLBCL or PMBCL,” Alessandro Riva, MD, Gilead’s Executive Vice President, Oncology Therapeutics & Head, Cell Therapy, said in a statement. “The recommendation brings axicabtagene ciloleucel one step closer to adult patients who currently have few or no treatment options available to them and we are focused on providing access to this innovative treatment as quickly as possible.”

In the ZUMA-1 trial, patients were enrolled into 2 cohorts consisting of those with DLBCL (n = 77) and those with PMBCL or TFL (n = 24). Prior to infusion of axi-cel, a conditioning regimen of fludarabine and cyclophosphamide was administered. Axi-cel was administered as a single infusion of modified autologous T cells at a target dose of 2 x 10⁶ CAR-positive T cells/kg.

All patients had chemorefractory disease and had received a median of 3 prior lines of therapy, with 54% refractory to 2 consecutive lines of therapy. Overall, 79% of patients were refractory to their last line of chemotherapy without having received prior autologous stem cell transplant (ASCT) while the remainder had relapsed within 12 months of ASCT.

Those with DLBCL had an ORR of 82% and a CR rate of 49%. After 8.7 months of follow-up, the ORR in the DLBCL group was 36%, which included a CR rate of 31%. In the PMBCL/TFL group, the ORR was 83% and the CR rate was 71%. The 8.7-month ORR rate was 67%, with a CR rate of 63%.

Across all patients (N = 101), the median duration of response was 8.2 months. The median overall survival (OS) was not yet reached at the time of the analysis. The 6-month OS rate was 80%.

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%). Cytokine release syndrome occurred in 13% of patients and neurologic events were experienced by 28% of patients. To treat these events, 43% of patients received tocilizumab and 27% received corticosteroids.

There were 4 fatal events in the study, 3 of which were deemed related to axi-cel. The first 2 reported were from hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of CRS. In early May 2017, the company noted that a patient had died from cerebral edema in the setting of grade 3 CRS with multiorgan failure. The unrelated death was from pulmonary embolism.

The FDA approved axi-cel in October 2018 for adults with relapsed or refractory non-Hodgkin lymphoma. The approval was specifically for those with large B-cell lymphoma following 2 prior therapies, including for those with DLBCL. Additionally, the CAR T-cell therapy is indicated for PMBCL, high grade B-cell lymphoma, and DLBCL transformed from follicular lymphoma.

The approval included boxed warning regarding CRS. To address the risk of CRS and neurologic toxicities, the FDA approved axi-cel with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). Additionally, certification and training will be required before hospitals will be cleared to administer the T cell therapy. The required training will focus on identifying and managing CRS and neurologic toxicity.

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.