Sattva S. Neelapu, MD: Axicabtagene ciloleucel, also called axi-cel, was FDA approved earlier this year on October 18th for patients with adult large B-cell lymphoma who have failed at least 2 or more lines of therapy. So, this therapy can be used in at least 4 different subtypes of lymphoma, including diffused large B-cell lymphoma, primary mediastinal B-cell lymphoma, transformed follicular lymphoma, and hybrid B-cell lymphoma.

Axi-cel is the first CAR T-cell therapy ever approved for non-Hodgkin’s lymphoma. In fact, this is the first CAR product ever approved by the FDA for patients with aggressive B-cell non-Hodgkin’s lymphoma who have failed at least 2 or more lines of therapy. There’s another CAR T-cell therapy product that is also approved, but that’s for a different indication, for acute lymphoblastic leukemia. But for lymphoma, this is the first indication.

So, the ZUMA-1 study is a multi-centered trial of axi-cel in patients with aggressive B-cell non-Hodgkin’s lymphoma. The study was conducted at 22 different centers. It started off as a phase I trial, maybe treated 7 patients, and then we extended it to a phase II trial for registration, maybe treated 101 patients. To be eligible for this trial, these patients had to have refractory diffused live B-cell lymphoma, the standard B-cell lymphoma, or transformed follicular lymphoma. And we used a very stringent definition of refractoriness. These patients had to have stable disease or progressive disease to the last line of chemotherapy, or if they relapsed after a prior autotransplant, the relapse had to be within the first 12 months. The primary endpoint for the study is overall response rate, and the secondary endpoints included complete response rate, progression-free survival, and overall survival.

So, we treated a total of 108 patients. Once the patients have been enrolled initially, they need to undergo leukapheresis procedure to collect T cells from the patient. The product is then shipped to the company for manufacturing of the CD19 CAR T-cell therapy. And once we receive the product, the patients are given a conditioning chemotherapy with cyclophosphamide and fludarabine for 3 days. And after 2 days of rest, they’re hospitalized and receive axi-cel at a dose of 2 million CAR-positive cells per kilogram body weight. The minimum required time for hospitalization is 7 days, and the first tumor assessment is done at 30 days.

We now have a median follow-up of 15.4 months on the study, and at this point the best overall response rate is 82% and the best complete response rate is 58%. At a median follow-up of 15.4 months, remarkably 42% of the patients remain in complete remission and progression-free. In fact, we see a plateauing of the progression-free survival go at around the 6-month time point, suggesting that the majority of the patients who remained in remission at 6 months tend to stay in remission. And the median overall survival for these patients has not been reached.

At 15 months, 56% of the patients are alive. And that compares very favorably to existing therapies. With existing therapies in this highly refractive patient population, the response rates are less than 30%, and the complete response rates are less than 10%. The median survival for these patients is about 6 months. With axi-cel, we are seeing more than half the patients are still alive 1 year later.

What’s also important to note on this study is that the product could be manufactured for 99% of the patients, and the median time from the time of apheresis to the delivery of the product to the clinical site was 17 days. And that’s really essential for these patients because these patients have rapidly progressing disease. They have rapid turnaround time, for generation of this patient-specific cellular therapy is essential. And 91% of the patients who are enrolled were able to receive the product.

In a preliminary analysis of the study, we also tried to understand why certain patients progressed or relapsed after receiving axi-cel. And in the 21 patients who we analyzed, we obtained tumor biopsies at the time of progression. And we found about one-third of them had loss of the CD19 protein at the time of progression. In another two-thirds of the tumors, we also found an upregulation of a marker called PD-L1, which is an inhibitory ligand that can inhibit the function of the CAR T cells. So, what this suggests is that there are at least 2 potential mechanisms of resistance, and this could potentially guide us on future therapies. For example, if the tumor loses CD19, one can envision targeting these tumors with a different antigen. Or in the future, one may envision developing bispecific CARs targeting both CD19 and the other proteins such as CD20 or CD22, for example.

And similarly, because there’s an upregulation of this inhibitory ligand that can suppress the function of CAR T cells, one can also envision doing a combination trial with axi-cel with the PD-1- or PD-L1-blocking antibody. And in fact, there’s a ZUMA-6 trial that is currently ongoing. We are testing that. We administered axi-cel in combination with atezolizumab, which is a PD-L1 antibody, and the results of the study are also being presented this week at the ASH meeting.

Transcript Edited for Clarity