Phase II ZUMA-2 Study Shows Promising Safety and Efficacy Results for KTE-X19

A 1-year follow-up of the phase II ZUMA-2 study, published in The New England Journal of Medicine, found that KTE-X19, an anti-CD19 CAR T-cell therapy, induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma (MCL).¹

Moreover, the trial therapy led to serious and life-threatening toxic events that were consistent with those previously reported in studies of anti-CD19 CAR T-cell therapies in patients with aggressive B-cell lymphoma. 

“ZUMA-2 is the first multicenter, phase II study of CAR T-cell therapy for relapsed/refractory mantle cell lymphoma, and these efficacy and safety results are encouraging,” Michael Wang, MD, professor of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, said in a press release.²“Although this study continues, our reported results, including a manageable safety profile, point to this therapy as an effective and viable option for patients with relapsed or refractory mantle cell lymphoma.”

In this multi-center trial, researchers enrolled 74 patients with relapsed or refractory MCL. The participants had disease that had relapsed or was refractory after the receipt of up to 5 previous therapies, and all patients had previously received BTK inhibitor therapy. The primary end point was the percentage of patients with an objective response (complete or partial), which was assessed by an independent radiologic review committee according to the Lugano classification.

Secondary endpoints included the duration of response, progression-free survival (PFS), overall survival (OS), the percentage of patients with an investigator-assessed objective response, the incidence of adverse events, the levels of CAR T-cells in the blood and cytokines in the serum, and changes in scores from baseline to month 6.

The patients underwent leukapheresis and optional bridging therapy, followed by a conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2x10⁶ CAR T-cells per kilogram of body weight. According to the protocol, the primary efficacy analysis was conducted after 60 patients had been treated and followed for 7 months. 

KTE-X19 was manufactured for 71 patients and administered to 68 of the participants. The primary efficacy analysis found that 93% (95% CI, 84-98) of the 60 patients in the analysis had an objective response and 67% (95% CI, 53-78) had a complete response. Moreover, in an intention-to-treat analysis which involved all 74 patients, 85% had an objective response and 59% had a complete response.

“All the patients who had an objective response after CAR T-cell infusion had robust T-cell expansion and also had B-cell aplasia at the first assessment, in contrast to the patients who did not have an objective response,” the authors wrote. “The percentages of patients with a response were also similar regardless of exposure to bridging therapy.”

At a median follow-up of 12.3 months (range, 7.0-32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated PFS and OS were 61% and 83%, respectively.

Further, common adverse events of grade 3 or higher observed were cytopenias (in 94% of the patients) and infections (in 32%). Additionally, grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively, though none were fatal. Only 2 grade 5 infectious adverse events occurred.

“The recovery of B cells in patients with mantle-cell lymphoma in our trial is consistent with that reported previously with anti-CD19 CAR T-cell therapy in patients with refractory large B-cell lymphoma, which suggests that durable responses may not depend on long-term persistence of functional CAR T-cells,” the authors wrote. 

According to the study, data are limited regarding other treatment approaches for relapsed or refractory mantle-cell lymphoma in patients who have received a BTK inhibitor, though single-agent venetoclax (Venclexta) and the R-BAC (rituximab [Rituxan], bendamustine [Bendeka], and cytarabine) have shown efficacy. 

References:

1. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med. doi:10.1056/NEJMoa1914347. 

2. Majority of patients responded in CAR T-cell trial for mantle cell lymphoma [news release]. MD Anderson. Published April 1, 2020. mdanderson.org/newsroom/majority-of-patients-responded-in-car-t-cell-trial-for-mantle-cell-lymphoma.h00-159381156.html. Accessed April 2, 2020.