Frederick L. Locke, MD, discusses the initial data for axicabtagene ciloleucel (axi-cel; Yescarta) plus atezolizumab (Tecentriq) in diffuse large B-cell lymphoma, and reflected on the long-term survival data from the ZUMA-1 trial.
Frederick L. Locke, MD
The combination of axicabtagene ciloleucel (axi-cel; Yescarta) and atezolizumab (Tecentriq) was deemed to be active and have a manageable safety profile in patients with refractory diffuse large B-cell lymphoma (DLBCL), according to findings from the phase I/II ZUMA-6 trial presented at the 2017 ASH Annual Meeting.
Toxicities reported in ZUMA-6 were similar to what was seen in the pivotal ZUMA-1 trial, said lead author Frederick L. Locke, MD. The overall response rate in the 9-patient phase I portion of ZUMA-6 was 89% (n = 8), including a complete response (CR) rate of 56% (n = 5).
ZUMA-6 is designed to follow the promising findings of ZUMA-1, where the CR rate was 40% at a median follow-up of 15.4 months for patients with refractory, aggressive, non-Hodgkin lymphoma treated with the chimeric antigen receptor (CAR) T-cell therapy axi-cel.
The long-term findings of the ZUMA-1 trial were also presented at the meeting, showing that 42% of patients treated with axi-cel remained progression free and 56% were alive. The 18-month progression-free survival rate was 41% and the 18-month overall survival rate was 52%. Based on initial data from the ZUMA-1 trial, the FDA approved axi-cel in October 2017 as a treatment for adult patients with relapsed or refractory non-Hodgkin lymphoma.
In an interview with OncLive, Locke, a medical oncologist at Moffitt Cancer Center, discussed the initial data for axi-cel plus atezolizumab in DLBCL and reflected on the long-term survival data from the ZUMA-1 trial.Locke: The ZUMA-6 study is a trial combining the CD19-directed CAR T-cell therapy axi-cel with the PD-L1 antibody atezolizumab. This trial is enrolling patients with DLBCL who did not respond to their last line of chemotherapy or who progressed within 12 months of an autologous hematopoietic stem cell transplant.
The study was designed to give atezolizumab after the CAR T-cell therapy, so we know that there is PD-L1 in the tumor microenvironment; there is PD-L1 on the CAR T cells themselves shorty after infusion. There is upregulation of other checkpoint genes within the tumor microenvironment within the first 3 weeks after therapy. Therefore, combining CAR T cells with blockade made sense. The toxicities associated with axi-cel were similar to what was seen in the pivotal ZUMA-1 clinical trial. There were similar rates of cytokine release syndrome (CRS) and neurologic toxicity. One patient out of 9 experienced a dose-limiting toxicity.
The study was designed to give PD-L1 shortly after CAR T-cell therapy, with the first 3-patient cohort receiving atezolizumab at day 21—4 doses were given 3 weeks apart. Cohort 2 was moved up to start at day 14 after CAR T-cell therapy. Then, in the third cohort, atezolizumab was given 1 day after CAR T-cell therapy infusion.
Therefore, when we evaluate safety, we try to determine if the combination increases toxicity rates. The patients who had severe CRS and neurologic toxicity actually had it before infusion of atezolizumab; it was really not associated with the combination. Again, 1 patient had a dose-limiting toxicity, and that patient had prolonged cytopenias beyond day 30—beyond CAR T-cell therapy. Because of that, we have enrolled 3 additional patients onto the third cohort. The next step is to expand it into a phase II trial. We want to find the safe schedule to combine these therapies. Once we have settled on a dosing schedule, we will expand it to another 22 patients and see if it improves the efficacy of the therapy compared with the patients with DLBCL who were treated on the ZUMA-1 trial as a control. One interesting thing that we found, by looking at the biomarkers, is that there is a trend toward an increase in the number of CAR T cells in the peripheral blood following the combination of CAR T-cell therapy and atezolizumab. We look forward to opening it up to a phase II trial to see if the combination can improve the efficacy of CAR T-cell therapy for DLBCL.
From the entire set of patients, the toxicities from axi-cel were consistent with the ZUMA-1 trial, so it does not seem that the combination increases the rate of toxicity of CAR T-cell therapy. Thus far, this combination seems to be tolerable, but we need to settle on a dosing schedule.ZUMA-1 is a multicenter clinical trial testing out the CD19-directed CAR T-cell therapy axi-cel. At the meeting, my colleague Dr Sattva Neelapu presented the long-term follow-up results that led to the FDA approval of the therapy for patients with DLBCL. This is a 15-month median follow-up for patients on the ZUMA-1 trial. We are actually showing results from 108 patients; this combines the 7 patients enrolled on the phase I trial and the 101 patients treated on the phase II trial. Of those 108 patients, with a 15.4-month median follow-up, 42% remain in response—which is quite remarkable.
Patients seem to have durable responses, as 40% of them achieved a complete response. For patients who achieved a CR, the median duration of response for those patients has not been reached. Therefore, a patient with DLBCL who experiences a CR with axi-cel therapy could remain in remission for many months and potentially years. In fact, patients treated at the National Cancer Institute with the same CAR T-cell therapy construct are in remission 4 years out and counting—so we think this therapy could really be durable for these patients.
The pivotal portion of the trial has completed enrollment, but we will continue to follow those patients for hopefully many, many years to come. It’s early. We have treated, to our knowledge, the first commercial patient at Moffitt Cancer Center and it’s a process similar to the clinical trial. We have to carefully select the patient and make sure they are fit and healthy enough to receive the therapy.
It is quite remarkable; these are patients who have no other options. We know from historical data that these patients have a very low chance of having a CR to standard chemotherapy; it is a 7% chance. Seeing CR rates of over 50% on the ZUMA-1 trial and durable responses in 42% of patients is pretty amazing. At the 2017 ASH Annual Meeting, we presented a safety management study for axi-cel designed to administer prophylactic levetiracetam and prophylactic tocilizumab (Actemra) to potentially prevent neurological toxicities and CRS. What we found is that prophylactic tocilizumab does appear to decrease the rate of severe CRS, and the rates of severe neurological toxicity were similar.
This study enrolled 34 patients. Patients received tocilizumab on day 2 after CAR T-cell infusion to prevent CRS and levetiracetam began on day 0 of CAR T-cell infusion. We are in process of updating the protocol and considering different schedules or different approaches to prevent those toxicities. However, it is very interesting that patients have lower severe CRS rates, and appear to have similar efficacy. It is also important to note that the level of CAR T cells in the blood were not different in patients who received theses prophylactic medications.
We also found some interesting data in the central nervous system (CNS). We paired CNS analyses before and after CAR T-cell therapy, and the patients with severe neurologic toxicity had elevation of key cytokines and chemokines, suggesting that the CAR T cells and myeloid cells are in the CNS secreting cytokines and are likely associated with those toxicities.