KTE-X19 Poised to Have Promising Future in MCL Paradigm

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?

Clinicians in the community will be struggling with having such an effective therapy at a significant cost. The toxicities that were witnessed in the ZUMA-2 study included a 30% neurotoxicity rate, and very similar grade 3 and higher CRS results; it really shows that the patients with MCL who have been so heavily pretreated were a challenge to treat. This therapy will continue to be used at experienced cell therapy centers.

If it is approved, where could KTE-X19 fit best into the treatment landscape?

The role of where we will position CAR T-cell therapy in the armamentarium of MCL, which has platinum-based therapies, ibrutinib-based therapies, rituximab (Rituxan), rituximab maintenance, anti-CD20 maintenance, autologous stem cell transplant, and venetoclax will be complicated. The challenge is that not only is CAR T-cell therapy trying to find its position [in the paradigm], but so is ibrutinib. Ibrutinib is now being tested in numerous clinical trials as part of upfront therapy for patients with MCL. The answer is, “We just don’t know.”

The submission indication [for KTE-X19] is in the third-line setting for those patients who previously failed or are refractory/intolerant to BTK-targeted therapy. The challenge for the FDA now is what should the indication be in a rapidly evolving paradigm. I won’t predict what the indication will be until I read it on the FDA website. There are a lot of possible uses for this therapy.

What are the next steps?

While we await the FDA to decide on the indication, price, and other things, there is an expanded access trial that is available at the same centers that brought the ZUMA-2 opportunity. You can continue to refer patients to those centers at this time where they will be treated on a trial with close data acquisition for both clinical and adverse event collection. There is a bridge while we await the FDA’s decision to help the patients who are very desperate [for treatment]. We have few other therapies for those who are intolerant or refractory to BTK inhibition.

References

1. Wang ML, Munoz J, Goy A, et al. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in patients (pts) with relapsed/refractory (r/r) mantle cell lymphoma (MCL): results of the phase 2 zuma-2 study. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract 754.
2. Wang ML, Munoz J, Goy A, et al. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in patients (pts) with relapsed/refractory (r/r) mantle cell lymphoma (MCL): results of the phase 2 zuma-2 study. Presented at: 2020 Transplantation and Cellular Therapies Meeting, Orlando, FL, February 19-23, 2020. Abstract 1.

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