Wang Weighs in on Promising Pharmacological Profile of KTE-X19 in High- and Low-Risk MCL

Michael Wang, MD

The autologous anti-CD19 CAR T-cell therapy KTE-X19 demonstrated comparable pharmacology and clinical outcomes in patients with lower- and higher-risk mantle cell lymphoma (MCL), according to Michael Wang, MD, who added that while the profile of the product was associated with efficacy, it was also linked with treatment-related neurologic events.

“We wanted to see whether the CAR T-cell expansion [would] be similar between high-risk and low-risk groups. We hoped they would be the same, and they actually are. That’s why the efficacy is also the same between these groups,” said Wang. “Now, we have underlying data to correspond with the observation that low- and high-risk [patients experience] the same [benefit] with this CAR T-cell therapy, [indicating the potential to] overcome the high risk of resistance. These are very powerful data.”

Data from the phase 2 trial demonstrated an objective response rate (ORR) of 93% with KTE-X19, with 67% of patients experiencing a complete response (CR). Data from acomparative analysis of the pharmacology profile of the product in high-risk versus low-risk patients were presented at the 2020 ASCO Virtual Scientific Program.

Results from the analysis showed that the pharmacokinetic and pharmacodynamic profiles of the product were comparable across patient groups with different prognostic marker status associated with lower and higher risk, which proved consistent with comparable clinical response rates. Additionally, the pharmacodynamic profile of KTE-X19 was linked with efficacy and grade 4 treatment-emergent neurologic events.

“Please remember that very good cytokine increase, which was caused by T-cell expansion, does not only cause good efficacy, but also increased neurotoxicity,” said Wang. “This is another challenge [that we face]. In the future, [I hope that] we can use these data to [determine a way to] interrogate the cytokines so that we can preserve the efficacy but decrease the neurotoxicity.”

In an interview with OncLive, Wang, a professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, further discussed data regarding the pharmacological profile of KTE-X19, the significance of these findings, and the next steps for this research.

OncLive: Could you provide an overview of the ZUMA-2 trial?

Wang: In MCL, we have recently developed the CD19 CAR T-cell therapy with Kite Pharma called KTE-X19. At the 2019 ASH Annual Meeting, we shared some exciting data on this cell therapy modality in treating patients with relapsed MCL. The results from that primary efficacy and safety analysis were remarkable. The current analysis focused on the T cell expansion, cytokine changes, T cell differentiation, and product characteristics of [the agent in] patients—low-risk and high-risk—on that same clinical trial. This is a very data-heavy poster and we are very happy to share the data with [OncLive].

Could you expand on the data that have led up to this comparative analysis?

We all know the pivotal phase 2 ZUMA-2 study evaluated KTE-X19 in patients with MCL who are relapsed/refractory to 1 to 5 prior lines of therapy, including a BTK inhibitor. In the primary analysis of ZUMA-2, which was presented at ASH, the ORR was 93%—very remarkable and unprecedented. We saw a very high CR rate of 67%. This was after a median of 3 prior lines of therapy with a follow-up of 12.3 months. A major question is whether CAR T-cell therapy could overcome disease associated with a poor combination of prognostic factors, such as Ki-67 and TP53 mutations.

We know that conventional therapies [such as], chemotherapy and targeted therapies, [are effective in patients] with low-risk MCL; they can induce high response rates and [achieve] very durable, long-term remissions. However, [patients with] high-risk factors, including high Ki-67 over 50% and a TP53 mutation, will not do very well [with those approaches]. In the primary analysis, we did not observe a significant difference between the safety and toxicities among these good- and poor-risk factor groups. This is remarkable because we do not want the therapy to discriminate against the high-risk factor [groups]. In the primary analysis, there's no difference [with regard to] efficacy, CR rate, and ORR between the low- and high-risk groups.

The ideal outcome is that [the profiles] come out the same. If they are different, [it could be that the patient] has a better profile [if they’re] low risk versus a poorer profile if they’re high risk; that's not good. That means the CAR T-cell therapy will be similar to [what has been seen with] chemotherapy and targeted therapies, where low-risk [patients] had good results and high-risk [patients] had bad results. However, if they are found to be the same in the correlative studies, we will know that we have found a therapy that will be similarly powerful and effective for both the poor- and high-risk groups. Therefore, we would be able to overcome the [challenges faced in effectively treating] high-risk group. This is a very exciting study poster.

What did the results from the present analysis show?

In the present analysis, we first compared the pharmacological profile of KTX-19 in low- and high-risk groups. Low-risk means without a TP53 mutation and a Ki-67 less than 50%. High-risk means that [patients have a] Ki-67 proliferation index of more than 50% with TP53 mutations. We showed that the KTX-19 product features were generally similar between high and low-risk groups. Again, that shows that [the features] do not discriminate against high-risk versus low-risk groups. There was a little trend observed with regard to high Ki-67 with CD4-based phenotypes, but the difference [was not statistically significant].

We also showed that the peak levels of AUC of CAR T-cells in the blood were comparable in patients with a wild-type versus mutated TP53. Basically, in both low-risk and high-risk patients, peak levels and [AUC of CAR T cells in the blood] are the same. When we infuse the CAR T-cells into the blood, the CAR T will proliferate in the blood, and they can expand to 6 million cells. The more the CAR T-cells expand, the better the efficacy, and the worse the toxicity. That was the primary analysis; in this analysis, we wanted to see whether the CAR T-cell expansion will be similar in high- and low-risk groups, and it was.

Additionally, we showed the pharmacodynamic profiles compared between low- and high-risk groups. Again, similar features [were demonstrated] between the 2 groups with a little trend toward increased cytokines in the high-risk group, but they were not determined to be statistically different. Building on the previously reported association between the pharmacological profile of KTE-X19 and ORR, in other words, the higher the CAR T-cell expansion, the higher the possibility of MRD negativity. If there's a high expansion of T cells, the MRD will be negative. In the primary analysis, we showed that the better the CAR T-cell expansion, the higher the MRD negativity; the lower the CAR T-cell expansion, the less MRD negativity. We also showed that cytokines, such as interferon-alpha, are elevated when the T cell has more expansion, and in this group, the MRD is negative. As such, cytokines are also positively correlated with MRD negativity, which is another very powerful observation.

Finally, we also characterized the pharmacokinetic profile of the 6 patients with a TP53 mutation. It is my pleasure to say that all [of these patients] have experienced good CAR T-cell expansion, they are MRD negative, and all have achieved a complete remission. Therefore, this CAR T-cell therapy has the initial evidence supporting that it can overcome high-risk factors, such as TP53 mutation.

In conclusion, we showed that the pharmacodynamic profiles of KTE-X19 were generally similar between the low- and high-risk groups. In addition, we showed that the pharmacodynamic profile of KTX-19 was associated with efficacy, including early MRD-negative status, but it also showed that the cytokines are higher in the grade 3 and 4 neurotoxicity events. In other words, cytokines increased together with the T-cell expansion; that does not only result in high efficacy but also increased toxicity—especially neurological toxicities.

Altogether, our pharmacological data support the concept that [this] CAR T-cell therapy could overcome MCL in the relapse setting [in those] with high-risk disease, especially when their Ki-67 is high and they have mutated TP53.

Are these cytokines predictive in terms of efficacy and safety outcomes for patients?

Some of the cytokines, the MRD data, were [identified at] day 28, so 28 days after the CAR T-cell was infused. We already know what's going to happen in 6 months and the next year. We already know that the cytokines can be predictive of the depth of response and how severe the neurological toxicity will be. Not only does this explained how the data are consistent with the efficacy and MRD, but we also know how long the neurotoxicity will last and how deep the [response will be], so [these data are] very [promising].

Reference

1. Wang M, Rossi JM, Munoz J, et al. Product characteristics and pharmacological profile of KTE-X19 in patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL) in the phase II registrational ZUMA-2 trial. J Clin Oncol. 2020;38(suppl 15):3023. doi:10.1200/JCO.2020.38.15_suppl.302