FDA Approval Sought for KTE-X19 in Relapsed/Refractory Mantle Cell Lymphoma


A biologics license application has been submitted to the FDA for the investigational CAR T-cell therapy KTE-X19 as a treatment for adult patients with relapsed/refractory mantle cell lymphoma.

Ken Takeshita, MD, global head of Clinical Development, Kite

Ken Takeshita, MD, global head of Clinical Development, Kite

Ken Takeshita, MD

A biologics license application has been submitted to the FDA for the investigational CAR T-cell therapy KTE-X19 as a treatment for adult patients with relapsed/refractory mantle cell lymphoma (MCL).1

The application is based on findings from the phase II ZUMA-2 trial, which were recently presented at the 2019 ASH Annual Meeting.2 Results showed a single infusion of KTE-X19 elicited an overall response rate (ORR) of 93%, as well as a complete response (CR) rate of 67% as assessed by an Independent Radiologic Review Committee.

“There remains a significant need for new treatments for patients with relapsed/refractory MCL despite recent advances, so this regulatory filing is an especially important milestone for the MCL community,” Ken Takeshita, MD, global head of Clinical Development, Kite, which is a Gilead Sciences company, stated in a press release. “We look forward to working with the FDA to bring KTE-X19 to appropriate patients as quickly as possible and continuing to deliver on the promise of our industry-leading cell therapy development program with a second CAR T therapy.”

Additionally, the company stated in the press release that it plans to submit a Marketing Authorization Application for KTE-X19 in the European Union in early 2020. KTE-X19 has also received a breakthrough therapy designation by the FDA and Priority Medicines by the European Medicines Agency as a treatment for patients with relapsed/refractory MCL.

KTE-X19 consists of an anti-CD19 single-chain variable fragment with a CD3 zeta T-cell activation domain and a CD28 signaling domain. During the manufacturing process, circulating tumor cells are separated from autologous immune cells.

Seventy-four patients were enrolled and underwent leukapheresis in the study, with 5 patients not receiving the therapy due to manufacturing failures (n = 3) or death from progressive disease (n = 2). Overall, 69 patients went on to receive conditioning chemotherapy with 68 received KTE-X19. The primary efficacy analysis presented at ASH was conducted on the first 60 patients enrolled in the study. Overall, KTE-X19 was effectively manufactured for 96% of patients and administered to 92%. The median time from leukapheresis to delivery of KTE-X19 was 16 days.

During the manufacturing process, patients in the study were allowed to receive bridging therapy for progressive disease at the investigator’s discretion. This could include ibrutinib (Imbruvica), acalabrutinib (Calquence), or dexamethasone, but not chemotherapy. Beginning 5 days prior to T-cell infusion, patients received 3 consecutive days of conditioning chemotherapy with fludarabine at 30 mg/m2 plus cyclophosphamide at 500 mg/m2. KTE-X19 was administered at 2 x 106 cells as a single infusion.

The median age of patients was 65 years, with 57% aged ≥65 years. Most patients had stage IV disease (85%) and 56% were intermediate or high-risk. The Ki-67 proliferation index was ≥50% in 69% of patients and 17% had TP53 mutations. Bone marrow involvement was found in 54% of patients, and 56% had extranodal disease. The most common morphologies were classical (59%), blastoid (25%), and pleomorphic (6%).

Patients had received a median of 3 prior therapies, with the majority having ≥3 treatments (81%). Almost all patients had received prior anthracycline or bendamustine and 100% of patients had received a prior anti-CD20 antibody. BTK inhibitors had been received by 100% of patients prior to study entry. Thirty-seven percent of patients received bridging therapy, most commonly with ibrutinib (21%). Of those who received bridging therapy, most had higher disease burden prior to infusion of the CAR T cells compared with baseline (92%).

Results showed that, at median follow-up of 12.3 months (range, 7.0-32.3), 47% of patients had been followed for ≥24 months. Forty percent of patients who initially had a partial remission (PR) or stable disease transitioned to CRs, with a median time CR of 3 months (range, 0.9-9.3). There were no cases of grade 5 cytokine release syndrome (CRS) or neurotoxicity.

At the time of the analysis, the median duration of response had not yet been reached. Of those reaching a CR, 78% remained in remission at the time of the analysis. For the first 28 patients treated on the trial, the median follow-up was 27.0 months. In these patients, 43% of responders remained in remission, suggesting high durability of response with a plateau in the curve.

Moreover, the median progression-free survival (PFS) was not yet reached. The 12-month PFS rate was 61%, with a tail on the curve (95% CI, 45%-74%). Additionally, the median overall survival (OS) was also not reached, with a 12-month OS rate of 83% (95% CI, 71%-91%).

Regarding safety, the most frequent treatment-emergent adverse event (TEAEs) of any grade were pyrexia (94%), neutropenia (87%), thrombocytopenia (74%), anemia (68%), and hypotension (51%). Grade 4 TEAEs included neutropenia (69%), thrombocytopenia (35%), hypoxia (9%), and hypotension (3%). There were 2 grade 5 AEs: the first was pneumonia related to the conditioning therapy and the second was staphylococcal bacteremia due to post-conditioning therapy and the CAR T-cell infusion.

All-grade CRS occurred in 91% of patients, which was grade ≥3 in severity for 15% of patients. The majority of pyrexia, hypotension, and hypoxia events seen in the study were related to CRS. Management for CRS included tocilizumab (59%) or corticosteroids (22%). The median time to onset was 2 days and the median duration was 11 days. All events resolved.

All-grade neurotoxicity was experienced by 63% of patients treated with KTE-X19, with 31% having a grade ≥3 event. The most common symptoms were tremor (35%), encephalopathy (31%), and confusion (21%). This AE was managed with tocilizumab (26%) and corticosteroids (38%) and the median time to onset was 7 days with a median duration of 12 days.

There was one case of grade 4 cerebral edema in the study that was confirmed using MRI of the brain. Following intubation, this patient was treated with aggressive therapy, including tocilizumab (Actemra), siltuximab (Sylvant), high-dose steroids, intrathecal Ara C plus dexamethasone, mannitol, ventriculostomy, and IV rabbit anti-thymocyte globulin (ATG). The neurotoxicity fully resolved for this individual and the CR had remained ongoing for 24 months at the data cutoff.


  1. Kite submits biologics license application to U.S. Food and Drug Administration for company’s second CAR T cell therapy. Gilead. Published December 11, 2019. Accessed December 11, 2019.
  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: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract 754.
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