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.
OncLive: Can you provide some background on the ZUMA-6 trial?
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.
What were the safety findings?
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.
What are the next steps?
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.