Axicabtagene Ciloleucel Emerges as Potential Standard for Some NHL Patients

Sattva S. Neelapu, MD

The FDA granted a priority review in May to axicabtagene ciloleucel (KTE-C19; axi-cel) for transplant-ineligible patients with relapsed/refractory non-Hodgkin lymphoma (NHL), based on results from the phase II ZUMA-1 trial. The agency is scheduled to make a final approval decision by November 29.

OncLive: Can you please provide an overview of the primary analysis of the ZUMA-1 trial?

As the FDA considers the axi-cel data, OncLive sat down with ZUMA-1 investigator Sattva S. Neelapu, MD, at the 2017 International Conference on Malignant Lymphoma biennial meeting in Lugano, Switzerland. Neelapu, an associate professor in the Department of Lymphoma/Myeloma, Division of Cancer Medicine, at the University of Texas MD Anderson Cancer Center, discussed the chimeric antigen receptor (CAR) T-cell therapy’s potential as a new standard of care for certain patients with NHL.Neelapu: Axi-cel is an autologous CAR T-cell therapy product that has CD3 zeta and CD28 signaling domains, that, when activated, will eliminate any CD19 expressing cells. We evaluated axi-cel in patients with refractory aggressive Hodgkin lymphoma that have a significant unmet clinical need. With existing therapies in these patients, the overall response rate is 26% and the complete response rate is only 8%, with a median survival being only 6.6 months.

On the ZUMA-1 multicenter phase II trial, we evaluated axi-cel in patients with refractory aggressive NHL. This is a phase II trial and we presented the primary results from this portion of the study. There were 2 cohorts in the study. Cohort 1 included patients with diffuse large B-cell lymphoma and cohort 2 included patients with primary mediastinal B-cell lymphoma and transformed follicular lymphoma.

To be eligible for this trial, patients had to have chemotherapy refractory disease that was defined as not having any response with the last line of chemotherapy or relapsing within 12 months after autologous stem cell transplantation. They should have had prior therapy with anti-CD20 monoclonal antibody and anthracycline therapy.

What were the grade 3 and above toxicities?

What are the next steps?

The primary endpoint for the trial was overall response rate in patients treated with axi-cel. The study met its primary endpoint for overall response rate with a P value of less than .0001. We observed that of 101 patients who were enrolled in the study, the overall response rate was 82% and the complete response rate was 54%. The responses were quite durable. At a median follow-up of 8.7 months, 44% of the patients had ongoing response. The median overall survival has not been reached at this point. At 6 months, we found that 80% of the patients that were treated on this trial were alive compared with only 55% of patients treated with existing therapies. As expected, we observed 2 common toxicities after CAR T-cell therapy: cytokine release syndrome and neurological toxicities. Grade 3 or higher cytokine release syndrome was observed in 13% of the patients and grade 3 or higher neurological events were observed in 28% of the patients. We also found that 3 patients had grade 5 events, related to cytokine release syndrome. The neurological events were completely reversible except in 1 patient who had an ongoing grade 1 memory impairment. I think these results are very encouraging for these patients, who have a significant unmet need. More than 40% of patients have durable response with this therapy. However, we need to find out why some patients either relapse or progress after axi-cel therapy. We need to look at whether there is an antigen escape in patients who relapse or progress, in which case we need to develop a new CAR T-cell therapy product against a different target.

Are there any ongoing trials addressing those next steps?

We are also looking at strategies to improve the efficacy of this product by combining it with immune checkpoint inhibitors like PD-1/PD-L1 blockade agents. We are also thinking about other combination trials.There is 1 ongoing trial with axi-cel in combination with a PD-L1 antibody. We are also looking at axi-cel in other subtypes of lymphomas, such as indolent lymphoma and mantle cell lymphoma. Those trials are ongoing, as well.

Are there any other challenges that you would like to see addressed in this space?

In the ZUMA-1 study, we evaluated this product in the third-line setting and beyond in patients with aggressive lymphomas. There is probably also value in looking at this product in the second-line setting of patients with aggressive lymphomas when they relapse after initial therapy or are treated with salvage chemotherapy followed by autologous stem cell transplantation. We are in the process of initiating a trial where we are going to compare axi-cel therapy with autologous stem cell transplantation in the second-line setting.This therapy is quite unique compared to other existing therapies in cancer. Most cancer therapies are either chemotherapies, monoclonal antibodies, targeted therapies, or radiation therapy.

What are the main takeaways from your presentation on the ZUMA-1 trial?

Axi-cel is a cellular therapy. It has unique toxicities compared to chemotherapy such as cytokine release syndrome and neurological events are something that most physicians are not experienced in managing. I think as this product becomes a standard of care, there is a lot of education that will need to happen for physicians as well as nurses and other healthcare staff at various institutions. Most centers have to be trained to be able to administer this therapy just how we trained when transplant therapies were introduced. The ZUMA-1 study met its primary endpoint for overall response rate. Currently, 44% of the patients have an ongoing response in the chemotherapy-refractory patient population. The toxicities, cytokine release syndrome and neurological events were quite manageable and generally reversible in the majority of patients.

It’s also important to recognize that this product was manufactured for 99% of the patients with 70 pretreated refractory NHL patients with an average turnaround time of only 17 days. That is critical as we make this therapy the standard of care, because these patients have rapidly growing disease and we need to be able to get this product in time.

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.