It’s my pleasure to present to you on behalf of my co-authors the long-term follow-up of ZUMA-1, a pivotal trial of axicabtagene ciloleucel, also called axi-cel, in patients with refractory aggressive non-Hodgkin’s lymphoma. Here are my disclosures. What we are presenting today is the updated analysis on ZUMA-1 where we pooled data from the phase I portion of the study, where we treated seven patients, and the phase II where we treated 101 patients. To be eligible for this trial these patients had to have refractory diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma or transform follicular lymphoma. They should have had no response to the last chemotherapy or should have relapsed within twelve months after prior auto-transplant. They should have received adequate prior therapy with anti-CD20 monoclonal antibody and anthracycline-based chemotherapy regimen.

Following the manufacturing of the product these patients received low dose conditioning chemotherapy with cyclophosphamide and fludarabine and two days later received the axi-cel at a fixed dose of two million CAR positive cells per kilogram. Importantly, 99% of the patients who were enrolled had the product manufactured and 91% of the enrolled patients were dosed with axi-cel. So this pooled analysis had a total of 108 patients with a data cut-off of August 11th 2017 when we had a median follow-up of 15.4 months.

Here are the baseline characteristics. The majority of these patients were advanced stage disease with stage 3 or 4, had high risk disease in about half of the patients. These patients were heavily pre-treated with three or more prior lines of therapy. 74% of the patients were refractory to two or more prior lines of therapy and 23% of the patients relapsed post auto-transplant within twelve months. What this reflects is that three-quarters of these patients could never get to a transplant, highlighting the refractory nature of these patients. In addition, two-thirds of the patients were having progressive disease to the last line of therapy prior to study entry.

Here’s the updated analysis. On the left in this table you can see the primary analysis and the updated analysis of 108 patients with a median follow-up of 15.4 months. The best objective response rate was 82% and the CR rate was 58%. 42% of the responses are ongoing with 40% in complete remission. We’ve had some patients who had conversion from stable disease to partial remission and from partial remission and stable disease to complete remission up to 15 months post-infusion without additional therapy. The median time to conversion from PR to CR was 64 days.

The durability of these responses have been observed consistently across key co-variants, including advanced stage disease of these patients, the high risk or low risk did not matter, the refractory status of these patients did not matter, nor did the CD4 or the CD8 ratio of the product and whether the patients received tocilizumab or corticosteroids.

The median duration of response for all patients was 11.1 months and the median duration of response for the CR patients has not been reached. We’ve had three patients from the phase I trial who have an ongoing complete remission two years after infusion of a single infusion of axi-cel. At a median follow-up of 15.4 months 42% of the patients remain progression free and 56% remain alive. On the PFS curve you can see there’s a plateauing of the curve appearing around the six month time point. The median overall survival has not been reached. The estimated 18 month overall survival rate is 52%.

Here’s a summary of the adverse events. The adverse events on the primary analysis were previously presented. In this updated analysis of 108 patients the grade 3 or higher cytokine release syndrome was observed in 12% of the patients and grade 3 or higher neurological events were observed in 31% of the patients. There were four grade 5 adverse events. All of these adverse events have been previously reported; the one additional adverse event compared to the primary analysis was previously reported on the phase I portion of the study. Since the primary analysis of at least six months of follow-up there has been no new axi-cel related CRS or neurological events or grade 5 adverse events. Most patients experienced hypogammaglobulinemia and B-cell aplasia as expected with this therapy but only 8% of these patients received IVIG support.

This table summarises the serious adverse events that have been noted after the primary analysis of at least six months. We observed serious adverse events in ten patients but the majority of these were infections. These infections, as well as other adverse events, had all resolved by the time of the data cut-off.

In conclusion, at a median follow-up of 15.4 months 42% of the patients have ongoing remission and the median duration of response for the CR patients has not been reached. The median overall survival has also not been reached at this point. Late onset adverse events for primarily infections and were quite manageable. There was no late onset CRS or neurological events that were noted related to axi-cel therapy. We also did not observe any replication recombinant retrovirus or insertional mutagenesis. Durable responses were observed with and without detectable persistent CAR T-cells in these patients.

In preliminary analysis of biopsies at the time of progression we observed at least two potential mechanisms of relapse, one due to CD19 loss and a second due to possible immune checkpoint expression such as PD-L1. In summary, these results suggest that axi-cel is highly effective in patients with large B-cell lymphoma who otherwise have no curative treatment options. These results are now published online on the New England Journal of Medicine website as of today.

With that, I’d like to acknowledge the patients and the families who participated in the study, the study staff and the healthcare professionals at the various institutions and the funding support from Kite and the Leukaemia and Lymphoma Society. Thank you for your attention.