EU Approval Sought for Axicabtagene Ciloleucel in Non-Hodgkin Lymphoma

Arie Belldegrun, MD

Kite Pharma has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for axicabtagene ciloleucel (axi-cel) to treat 3 forms of non-Hodgkin lymphoma (NHL).

Axi-cel, an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, would be the first CAR T-cell therapy approved for use in Europe, according to Kite. The FDA is currently reviewing the treatment and is scheduled to make its decision on or before November 29, 2017.

Kite is seeking to market axi-cel for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL) who are ineligible for autologous stem cell transplant.

“The MAA submission of axicabtagene ciloleucel marks an important global milestone in the development of engineered T-cell therapy,” Arie Belldegrun, MD, Kite chairman, president, and CEO, said in a press release. “We are excited to work closely with the EMA, Committee for Medicinal Products for Human Use, and Committee for Advanced Therapies to help bring this potentially transformative therapy to patients in the EU.”

Kite submitted data from the phase II ZUMA-1 trial, which were previously presented at the 2017 International Conference on Malignant Lymphoma biennial meeting in Lugano, Switzerland, to support the MAA. The best overall response rate (ORR) in the modified intent-to-treat (mITT) population of 101 patients with NHL was 82% (P <.0001); of responding patients, 54% achieved complete response (CR) and 28% of patients achieved partial response (PR).

Response was durable at 8.7 months of follow-up with 44% of responding patients maintaining response and 39% of patients remaining in CR.

A cohort of 77 patients with DLBCL demonstrated an ORR of 82%, with 49% of these patients achieving CR. A second cohort of 20 patients with PMBCL or TFL demonstrated an ORR of 83%, with 71% of the responders achieving CR.

In the phase II ZUMA-1 trial, adult patients were enrolled in 2 cohorts consisting of 72 patients with DLBCL and 20 patients with PMBCL or TFL. Axi-cel was successfully manufactured in 110 (99%) patients, with an average turnaround time from apheresis to the clinical site of 17 days.

Following low-dose conditioning with cyclophosphamide/fludarabine, a target dose of 2 × 106 anti-CD19 CAR T cells was administered to 101 (91%) patients; the patients had a median age of 58 years (range, 23-76), 67% were male, 85% had stage III-IV disease, 47% had IPI 3-4, and 59% of patients were ECOG PS 0-1. Most (69%) patients had received 3 or more prior lines of treatment, 54% had been refractory to 2 consecutive lines of therapy, and 21% of patients had relapsed within 12 or fewer months of receiving an autologous stem cell transplant (ASCT). No bridging therapy was allowed in ZUMA-1.

The primary endpoint for this analysis was ORR in the combined DLBCL, PMBCL, and TFL population. Key secondary endpoints were duration of response (DOR), overall survival (OS), levels of CAR T and cytokines, and safety. The primary analysis was done when the first 92 patients treated had at least 6 months of follow-up.

Response rates were also consistent between DLBCL molecular subgroups based on the cell of origin, as determined by the Nanostring Lymphoma Subtyping Test. Of 69 patients with evaluable samples, 25% of patients had activating B-cell (ABC) subtype, 17% were germinal center B-cell (GCB) subtype, and 4% remained unclassified. The ORR was 75% in ABC patients and 88% in patients GCB subtype; of responding patients, 59% and 57% of ABC and GCB patients achieved CR, respectively. This CR is ongoing in 35% of ABC patients and 47% of GCB patients.

These responses were durable; at 8.7 months of follow-up, 44% of patients in the overall mITT population demonstrated an ongoing response and 39% of patients maintained CR. The median duration of response (DOR) was 8.2 months (95% CI, 3.3 months—not reached [NR]) in the overall population. The median DOR was not reached for patients achieving CR (95% CI, 8.2 months–NR), and the median DOR for PR was 1.9 months (95% CI, 1.5–2.1).

Median progression-free survival was 5.9 months (95% CI, 3.4—9.8), and median OS was not reached at a median follow-up of 8.7 months (95% CI, 10.5– NR). The 6-month OS rate was 80% in ZUMA-1.

The levels of CAR T-cells peaked within 7 to 14 days of axi-cel treatment. The expansion of CAR T-cells was associated with the ORR, area under the curve (AUC) fold = 5.4, and with the presence of grade ≥3 neurologic events, AUC fold = 2.6 but not with cytokine release syndrome (CRS), AUC fold = 1.3.

In the primary safety analysis of 101 patients, the most frequently occurring grade ≥3 adverse events (AEs) were anemia in 43% of patients, neutropenia (39%), decreased neutrophil count (32%), febrile neutropenia (32%), decrease white blood cell count (29%), thrombocytopenia (24%), encephalopathy (21%), and decreased lymphocyte count (20%).

The rate of CRS in the primary analysis showed a decrease to 13% from the rate demonstrated in the preliminary analysis; 43% of patients with CRS received tocilizumab and 27% received corticosteroids to resolve CRS. The rate of neurologic events was 28% in the primary assessment. Greater CAR T-cell levels were observed in patients requiring tocilizumab or steroids for AE management but no impact on response was noted.

Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel (AXI-CEL; KTE-C19) in patients with refractory aggressive non-Hodgkin Lymphomas (NHL): primary results of the pivotal trial ZUMA-1. Presented at: 14th International Conference on Malignant Lymphoma; June 14-17, 2017; Lugano, Switzerland. doi: 10.1002/hon.2437_7.