KTE-X19 Continues to Elicit Durable Responses in Relapsed/Refractory MCL

Michael L. Wang, MD

The CAR T-cell product KTE-X19 continues to demonstrate durable clinical benefit in patients with relapsed/refractory mantle cell lymphoma (MCL), with an overall response rate (ORR) of 92% (95% CI, 82%-97%), according to updated data from the phase 2 ZUMA-2 trial (NCT02601313) presented during the 2021 Transplantation & Cellular Therapy Meetings.¹

At a median follow-up of 17.5 months, the complete response (CR) rate with KTE-X19 was 67% (95% CI, 53%-78%; n = 40), and 70% (n = 28) of these patients continued to respond to treatment at the time of data cutoff. In all patients who were enrolled to the trial (n = 74), the ORR was 84%, with a CR rate of 59%.

“The ZUMA-2 study continues to show substantial and durable clinical benefit [with] KTE-X19 therapy in patients with relapsed/refractory MCL,” Michael L. Wang, MD, of The University of Texas MD Anderson Cancer Center, and colleagues, wrote in a poster on the data. “Ongoing response rates were largely consistent among patients with high-risk disease characteristics.”

Patients with relapsed/refractory MCL who experience disease progression following BTK inhibition are known to experience poor clinical outcomes; this population will only experience ORRs ranging from 25% to 42% and an overall survival (OS) ranging from 6 months to 10 months with salvage therapies.

In July 2020, the FDA approved KTE-X19 (now referred to as brexucabtagene autoleucel) for use in adult patients with relapsed/refractory MCL based on earlier data from ZUMA-2. Results from the primary analysis of the trial showed that the CAR T-cell product induced an ORR of 93%, with a CR rate of 67% in patients with MCL who were relapsed or refractory to 1 to 5 previous therapies, including a BTK inhibitor.²

The single-arm, open-label, phase 2 trial enrolled a total of 74 patients who underwent leukapheresis; 5 patients did not receive treatment because of manufacturing failures (n =3) or death from disease progression (n = 2). Sixty-nine participants went on to receive conditioning chemotherapy with intravenous (IV) fludarabine at 30 mg/m2 and cyclophosphamide at 500 mg/m2 on days -5, -4, and -3. Sixty-eight patients received the CAR T-cell therapy product at 2 x 106 cells/kg via IV infusion on day 0.

The primary end point of the trial was ORR per Independent Radiology Review Committee assessment and Lugano classification, while secondary end points included duration of response (DOR), progression-free survival (PFS), OS, safety, and levels of CAR T cells in the blood and cytokines in serum.

As of the data cutoff of December 31, 2019, 60 patients were determined to be efficacy evaluable. The first 28 patients who received treatment had a median follow-up of 32.3 months, and 39% of patients remained in continued remission without any further therapy required.

Additional data revealed that at a median follow-up of 17.5 months, the median DOR (95% CI, 14­–not estimable [NE]), median PFS (95% CI, 10-NE), and median OS (95% CI, NE-NE), had not yet been reached. The PFS rate at 15 months was 59% (95% CI, 45-71), while the OS rate at that time was 76% (95% CI, 63-85).

Moreover, peak CAR T-cell expansion proved to be higher in patients who had an ongoing response at 12 months or those who relapsed at 12 months versus nonresponders. However, additional ongoing mechanistic studies are being done to further understand the pharmacokinetic relationship between response to KTE-X19 and durability.

Eighty-four percent (n = 48) of the 57 efficacy-evaluable patients who had data available at baseline were observed to have detectable B cells at baseline. Investigators reported that participants who had ongoing responses to treatment at 12 months experienced an increase in B-cell recovery over time, while gene-marked CAR T cells were found to decrease over time. No link between CAR T-cell expansion measured within the 2 weeks after the infusion and B-cell aplasia was noted.

Safety data were reported for all 68 patients on the trial who received the CAR T-cell product and no new signals were reported with additional follow-up. Eighty-one percent of patients experienced any-grade toxicities, while 48% experienced effects that were grade 3 or higher in severity at 3 months post infusion; these rates were 72% and 37%, respectively, at 6 months post infusion.

The most commonly reported toxicities with KTE-X19 included anemia, neutropenia, thrombocytopenia, decreased white blood cell counts, fatigue, pneumonia, cough, hypogammaglobulinemia, and upper respiratory tract infection.

Notably, no new cases of cytokine release syndrome were observed since the prior report, nor grade 5 toxicities.

References

1. Wang ML, Munoz J, Goy A, et al. One-year follow-up of ZUMA-2, the multicenter, registrational study of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma. Presented at: 2021 Transplant & Cellular Therapy Meetings; February 8-12, 2021; Virtual. Poster 414.

2. 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. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347