The FDA has granted a priority review designation to a biologics license application for the investigational CAR T-cell therapy KTE-X19 as a treatment for adult patients with relapsed/refractory mantle cell lymphoma.
Ken Takeshita, MD
The FDA has granted a priority review designation to a biologics license application (BLA) for the investigational CAR T-cell therapy KTE-X19 as a treatment for adult patients with relapsed/refractory mantle cell lymphoma (MCL).1 The designation is based on findings from the phase II ZUMA-2 trial, in which a single infusion of the CAR T-cell product elicited a 93% objective response rate, as assessed by an Independent Radiologic Review Committee, in patients with relapsed/refractory MCL; additionally, there was a 67% complete response (CR) rate.2
Moreover, grade ≥3 cytokine release syndrome (CRS) and neurologic events were reported in 15% and 31% of patients, respectively, and no grade 5 CRS or neurologic events occurred.
Under the Prescription Drug User Fee Act, the FDA will make a decision on the BLA by August 10, 2020.
“Despite recent advances, patients with relapsed/refractory mantle cell lymphoma currently face a significant lack of effective treatment options once their disease no longer responds to currently available therapy,” Ken Takeshita, MD, Kite’s Global Head of Clinical Development, stated in a press release. “Based on the encouraging results for KTE-X19, we are eager to continue discussions with the FDA on how to bring this innovative treatment to these patients who may benefit from CAR T therapy.”
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.
In the single-arm, open-label ZUMA-2 study, 74 patients were enrolled and underwent leukapheresis, 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 and 68 received KTE-X19.
A primary efficacy analysis, which was presented at the 2019 ASH Annual Meeting, 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 as a single infusion at 2 x 106 cells.
The median age of patients was 65 years, with 57% of patients aged ≥65 years. Most patients had stage IV disease (85%) and 56% had intermediate- or high-risk disease. 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%).
Moreover, the median number of prior therapies was 3; the majority of patients (81%) had ≥3 treatments. Almost all patients had received prior anthracycline or bendamustine and 100% of patients had received a prior anti-CD20 antibody. BTK inhibitors had been given to 100% of patients prior to study entry. Furthermore, 37% 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%).
Additional results showed that, at a 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 to CR of 3 months (range, 0.9-9.3).
The median duration of response had not yet been reached at the time of the analysis. 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, which suggested high durability of response with a plateau in the curve.
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%). 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 events (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. The majority of pyrexia, hypotension, and hypoxia events seen in the study were related to CRS. Management for CRS included tocilizumab (Actemra; 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. 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, siltuximab (Sylvant), high-dose steroids, intrathecal cytarabine plus dexamethasone, mannitol, ventriculostomy, and IV rabbit anti-thymocyte globulin. The neurotoxicity fully resolved for this individual and the CR had remained ongoing for 24 months at the data cutoff.
Additionally, in January 2020, the European Medicines Agency (EMA) validated a Marketing Authorization Application for KTE-X19 as a treatment for adult patients with relapsed/refractory MCL. The CAR T-cell product has also been granted a breakthrough therapy designation by the FDA as well as PRIME designation by the EMA for use in this setting.