December 17, 2020 — The European Commission has granted a conditional marketing authorization to the CD19-targeted CAR T-cell therapy KTE-X19 for use in adult patients with relapsed or refractory mantle cell lymphoma who had previously received 2 or more lines of systemic therapy including a BTK inhibitor.
The European Commission has granted a conditional marketing authorization to the CD19-targeted CAR T-cell therapy KTE-X19 (Tecartus) for use in adult patients with relapsed or refractory mantle cell lymphoma (MCL) who had previously received 2 or more lines of systemic therapy including a BTK inhibitor.1
The authorization is supported by data from the phase 2 ZUMA-2 trial (NCT02601313), which showed that a single infusion of the product resulted in an overall response rate of 93% in patients with relapsed/refractory MCL, per independent radiologic review committee assessment, with 67% of patients experiencing a complete response (CR) to treatment.2
“Significant gaps in treatment remain for patients with MCL who progress following initial therapies,” John G. Gribben, professor, consultant hematologist, and medical oncologist at Barts and The London NHS Trust, stated in a press release. “The availability of this first cell therapy for relapsed or refractory MCL, following at least 2 lines of systemic therapy including a BTK inhibitor, provides an important option for patients in Europe.”
The single-arm, open-label phase 2 trial enrolled a total of 74 patients who underwent leukapheresis, with 5 patients not receiving the therapy either because of manufacturing failures (n = 3) or due to death from disease progression (n = 2). A total of 69 patients received conditioning chemotherapy and 68 of these patients were given the CAR T-cell product.3
Data from the first 60 patients enrolled to the trial were reported in the primary efficacy analysis during the 2019 ASH Annual Meeting. The therapy was found to be effectively manufactured in 96% of patients and was given to 92% of patients. A median time of 16 days from leukapheresis and the delivery of the agent was reported.
The median age of patients was 65 years and 57% were older. Additionally, 85% had stage IV disease, 56% had intermediate- or high-risk disease, and 69% had a Ki-67 proliferation index of 50% or greater. Additionally, 17% of patients had tumors that harbored TP53 mutations. Fifty-four percent of patients had bone marrow involvement, 56% had extranodal disease. Lastly, 59% had classical morphology, 25% had blastoid, and 6% had pleomorphic.
Participants had received a median of 3 previous treatments and the majority of patients, or 81%, had received 3 or more therapies. Most patients had received a prior anthracycline or bendamustine. All patients had previously received an anti-CD20 antibody and all had been exposed to BTK inhibitors prior to study initiation. Additionally, 37% of participants had received bridging therapy, with 21% of patients given ibrutinib (Imbruvica). Ninety-two percent of patients who received bridging therapy had a higher disease burden prior to the administration of the CAR T-cell product vs what was observed at baseline.
Forty percent of patients who initially experienced a partial remission or stable disease were able to transition over to CRs, and the median time to CR was 3 months. At the time of the analysis, the median duration of response with KTE-X19 had not yet been reached. More than three-fourths of patients, or 78%, who had achieved a CR with the therapy remained in remission.
For the first 28 patients who received treatment with the CAR T-cell product, the median follow-up was 27.0 months; 43% of this patient subset continued to be in remission.
At the time of the analysis, the median progression-free survival had not yet been reached with KTE-X19. At 12 months, the PFS rate in the experimental arm was 61%, with a tail on the curve (95% CI, 45%-74%). The median overall survival had also not been reached, but the OS rate at 12 months was 83% (95% CI, 71%-91%).
Regarding safety, among the most commonly experienced treatment-emergent adverse effects (TEAEs) were pyrexia (94%), neutropenia (87%), thrombocytopenia (74%), anemia (68%), and hypotension (51%). TEAEs that were grade 3 or higher in severity included neutropenia (69%), thrombocytopenia (35%), hypoxia (9%, and hypotension (3%). Two grade 5 toxicities were experienced; these events included pneumonia linked with conditioning treatment and staphylococcal bacteremia; these were both due to post-conditioning treatment and the CAR T-cell infusion. Ninety-one percent of participants reported all-grade cytokine release syndrome.
The pharmacodynamic profile of the CAR T-cell product was also found to be linked with efficacy and treatment-related neurological events, according to updated data shared during the 2020 ASCO Virtual Scientific Program.4
Additionally, when the product was compared with other options that have received regulatory approval in the space, it showed comparable pharmacologic and clinical outcomes in patients with high-risk disease features vs lower-risk characteristics, which were defined by tumor protein TP53 mutation or high Ki-67 proliferation index.
In July 2020, the FDA approved brexucabtagene autoleucel (Tecartus) for use in adult patients with relapsed/refractory MCL based on findings from ZUMA-2.