Frederick L. Locke, MD
The chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (KTE-C19) has shown very promising results in patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal lymphoma, and transformed follicular lymphoma. The findings were recently presented at the 2017 AACR Annual Meeting.
In the 101 patients enrolled on the ZUMA-1 trial, results showed that the objective response rate (ORR) was 82%, including a complete response (CR) rate of 54%. In the intent-to-treat population, the 6-month overall survival (OS) rate was 80%. Moreover, the ZUMA-1 findings have been submitted to the FDA to support a biologics license application for axicabtagene ciloleucel as a treatment for transplant-ineligible patients with relapsed or refractory aggressive non–Hodgkin lymphoma.
“The results of this clinical trial are really exciting to us,” said lead study author Frederick L. Locke, MD. “We have seen that 82% of patients can have a response to this single infusion; 54% of patients can have a CR, and 44% of patients are in an ongoing response at the time of the data cutoff. Perhaps, most interestingly, is that the 6-month OS rate on the ZUMA-1 study was 80%, which compares very favorably to the historical SCHOLAR-1 control with standard-of-care therapy, where the 6-month OS rate was 55%, suggesting that this therapy—a single infusion of CAR T cells—can positively impact overall survival.”
In an interview with OncLive
during the AACR meeting, Locke, a medical oncologist at Moffitt Cancer Center, discussed the ZUMA-1 trial and the next steps going forward.
OncLive: Please provide an overview of the primary ZUMA-1 analysis being presented here at the 2017 AACR Annual Meeting.
We're here at the 2017 AACR Annual Meeting to present the primary analysis of the ZUMA-1 clinical trial that includes both the clinical results and biomarker analyses—to look at biomarkers that correlate to toxicity or predict for efficacy.
The clinical trial enrolls patients with DLBCL, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma, who are truly chemorefractory to their last line of therapy, meaning they had no response to their last line of therapy or relapsed within 12 months of an autologous transplant.
Can you provide background to this study?
The primary endpoint of the clinical trial was to evaluate the ORR, with 1 treatment of CAR T cells called axicabtagene ciloleucel (Kite Pharma), which is formally called KTE-C19. Patients are to receive fludarabine, cytotoxic conditioning chemotherapy, and 1 single infusion of anti-CD19 CAR T cells of axicabtagene ciloleucel. The primary endpoint was to look at the response rate after this treatment, compared with a robust historical control called SCHOLAR-1, which is a more than 600-patient international meta-analysis looking at that same patient population with standard-of-care therapy. There were 111 patients enrolled on the clinical trial. Ninety-nine percent of those patients were able to have CAR T cells manufactured from there, so a 99% manufacturing success rate. There was a 17-day average turnaround time from the cells being shipped out to the centralized manufacturing facility and coming back to the treatment center. Of those 111 enrolled patients, 91% received infusion of axicabtagene ciloleucel. Of those 10 patients who didn’t get the treatment, the majority had adverse events (AEs) due to progressive disease that precluded them getting infusion of CAR T cells.
What were the results presented here?
The primary analysis was triggered when at least 92 patients had the opportunity for 6 months of follow-up. When the 92nd patient was dosed, there were an additional 9 patients already enrolled and so those patients went on to also receive the therapy. Therefore, 101 patients had received axicabtagene ciloleucel and those 101 patients are the modified intention-to-treat population that was prespecified in the protocol, and those are the results we are presenting. Out of those 101 patients, how did they do?
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.