Eighty-two percent of those patients had a response to the single infusion of axicabtagene ciloleucel, and 54% of those patients had a CR. This compares very favorably to the historical SCHOLAR-1 control, where we would expect 26% of patients to have a response and 8% to have a CR.
Let’s discuss safety. What were the AE results?
We expected toxicities due to this therapy, based upon the single-institution experiences. This is a 22 multicenter clinical trial, so we were looking out for 2 main categories of toxicity: cytokine release syndrome (CRS), which is categorized by high fever and low blood pressure, and we were also looking for neurologic events. This is confusion, delirium, and word-finding difficulties.
We found grade 3 or higher CRS in 13% of patients and grade 3 or higher neurologic events in 28% of patients. We actually found that, over time on the trial, these rates decreased and we think that is due to increased comfort with the investigators. Also, the really interesting finding is that the use of tocilizumab and corticosteroids to treat those toxicities associated with CAR T cells did not lower the response rates.
Patients who received tocilizumab and corticosteroids on this trial had similarly high response rates and similarly high CRs, so we think it is safe to administer those therapies to treat the side effects even earlier on in the disease course to prevent more serious toxicities. We think that those therapies don’t have an effect on the response rates or CR rates.
What are the next steps following these findings?
We are really excited about these results. In fact, the 6-month OS rate on this ZUMA-1 trial was 80% and that compares very favorably to the SCHOLAR-1 data of 55%, suggesting that we are actually having a positive impact on survival for these patients.
Many of these responses are durable. In fact, at the time of the data cutoff, 44% of patients remain in remission. We know from the phase I portion of this clinical trial—the safety portion—that these responses can be durable. In fact, in the phase I portion, 3 out of the 7 patients had a CR and those CRs are ongoing at 18 months. In the single-center experience at the National Cancer Institute that used the same CAR T-cell construct, there are patients at over 4 years out who remain in complete remission. We are continuing long-term follow-up.
Also, to answer your question, we want to figure out why this therapy doesn’t work for everyone. We are looking at additional biomarker analyses to figure out what will make this product work better and what can be added on.
We have presented some of the biomarker analyses here at the meeting. We have a separate abstract outside of the clinical results. What we found is that the peak expansion—the number of CAR T cells after infusion within the peripheral blood by quantitative pathologic complete response analysis and the number of CAR T cells over time in the first month after the cells are infused—corresponds to response rates. It also corresponds to grade 3 or higher neurologic AEs.
What else is so exciting about this trial?
Another interesting finding is that in patients who did obtain a CR, the median duration of response has not yet been reached. We have a lower bound at a 95% confidence interval of 8.2 months. Therefore, patients who have a CR are staying in response for a long period of time. We know from single-center experience and the phase I portion of this trial that these CRs can be durable for 18 months or longer.
It is important to note that the toxicities that we saw—CRS and neurological events—are generally reversible. These are going away within 1 month of the therapy, so we think that this is a therapy that can be safely administered across multiple centers for patients who are really without other treatment options. We were seeing durable clinical responses that we would not expect with standard-of-care treatment. And, the use of corticosteroids and tocilizumab to treat those side effects does not seem to have any impact on the efficacy of the therapy.
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.