David Miklos, MD
As the investigational CAR T-cell therapy KTE-X19 awaits FDA approval as a treatment for patients with relapsed/refractory mantle cell lymphoma (MCL), additional follow-up and analyses will determine the durability of responses the agent has elicited in patients and how it will best fit in the paradigm, according to David Miklos, MD.
In February 2020, the FDA granted a priority review designation to a biologics license application for KTE-X19 in this setting, based on data from the phase II ZUMA-2 trial.
At a median follow-up of 12.3 months, results showed that KTE-X19 demonstrated an objective response rate (ORR) of 93% in patients with relapsed/refractory MCL.1,2
A complete response (CR) rate of 67% was also observed.
With the use of CAR T-cell therapy, neurotoxicity and cytokine release syndrome (CRS) are of concern. In ZUMA-2, KTE-X19 was associated with a grade ≥3 CRS rate of 15% in patients, while grade ≥3 neurological events were observed in 31% of patients on the study.
“We will need additional long-term follow-up to determine the durability [of these responses], but [the fact that] 50% of patients are achieving durability is very promising,” said Miklos, an author on the ZUMA-2 trial. “The publications are underway, and the package [for approval of this therapy] has been submitted to the FDA.”
In an interview with OncLive
during the 2020 Transplantation & Cellular Therapy (TCT) Meetings, Miklos, associate professor of medicine at Stanford University, discussed the results from the ZUMA-2 trial evaluating KTE-X19 in patients with relapsed/refractory MCL.OncLive: Could you provide some background to KTE-X19?Miklos:
Using the same construct targeting CD19 with a CD28 costimulatory domain as axi-cel, KTE-X19 [was produced] with roughly the same type of processing—with the really important difference that they are isolating T cells using CD4+/CD8+ infinity isolation and then making products that are specific to T cells. This was the conversion; this was the important process of evolution for ZUMA-2 in patients with MCL who had failed 2 prior lines of therapy and were either ibrutinib [Imbruvica]-refractory or ibrutinib-intolerant.What were the findings of this study?
At the 2019 ASH Annual Meeting, and again here at the 2020 TCT Meetings, Michael Wang, MD, who is our lead author on the study, [shared these data]. I’ve been blessed to be a co-site investigator. At Stanford University, we were very enthusiastic to bring these patients forward. [This is a challenging patient population] because once they have failed ibrutinib, there is venetoclax (Venclexta) and other therapies, but there are no long-term remissions that have been seen in this patient population.
Along comes a clinical trial in which 68 patients have been treated, and the ORR was 93% with a 67% CR rate. The patients who had been followed for at least 2 years are showing 52% durable disease responses. In MCL, where a leukemic phase plays a very measurable aspect of lymphoma, we can apply blood next-generation sequencing technologies to detect down to 1 in 1 million the number of cancer cells. Those type of data have shown a significant 40% of patients undetectable MRD, and this allows us to follow for continuing type of anti–B-cell benefits of the CAR T-cell therapy.
These data are still an early publication at this point, with all patients out 1 year, and about half of them out at 2 years. The submission occurred with an expected action date of August 2020. This is very exciting, it will be a new therapy, and it will even have a new name.What is the safety profile of KTE-X19?
It’s important to emphasize that the toxicities that were experienced on ZUMA-2 were as significant as what we witnessed in ZUMA-1, with neurotoxicity of grade 3 or more and similar levels of grade 2 CRS occurring in at least 50% of these patients. Cytopenias and low blood cell counts are developing in roughly 50% of patients at day 28 or beyond.
The 3 known toxicities of CD19-directed CAR T-cell therapy, which is CRS, neurotoxicity, and cytopenias, delayed in the 28-day period, continue to be challenging for physicians trying to care for their patients. They aren’t worse than things that have already been experienced. An experienced transplant CAR T-cell therapy center will find it very manageable, but it’s going to be an in-patient therapy with an “all-hands-on-deck” attitude at experienced centers to deliver the same outcomes.What should community oncologists keep in mind about these data and this type of treatment?