FDA Submission for KTE-X19 Planned After High CR Rates Were Observed in MCL

December 10, 2019

Patients with relapsed/refractory mantle cell lymphoma experienced a 67% complete remission rate and an objective response rate of 93% after treatment with the anti-CD19 CAR T-cell therapy KTE-X19, according to findings from the phase II ZUMA-2 study presented at the 2019 American Society of Hematology ASH Annual Meeting.

Michael Wang, MD

Patients with relapsed/refractory mantle cell lymphoma (MCL) experienced a 67% complete remission (CR) rate and an objective response rate (ORR) of 93% after treatment with the anti-CD19 CAR T-cell therapy KTE-X19, according to findings from the phase II ZUMA-2 study presented at the 2019 American Society of Hematology (ASH) Annual Meeting.

The median follow-up at the analysis was 12.3 months (range, 7.0-32.3), with 47% of patients having 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.

Based on findings from the ZUMA-2 trial, Kite and Gilead plan to submit a biologics license application to the FDA within the next few weeks for KTE-X19 in relapsed/refractory MCL. A marketing authorization application will also be submitted to the European Medicines Agency (EMA) in the first quarter of 2020.

"KTE-X19, in a single infusion, demonstrates high rates of durable responses in relapsed/refractory mantle cell lymphoma," Michael L. Wang, MD, the University of Texas MD Anderson Cancer Center, said during a presentation of the results. "The 93% overall response rate, which includes a 67% CR rate, is the highest reported rate of disease response in patients with prior BTK inhibitor failure."

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, which differentiates KTE-X19 from axicabtagene ciloleucel (Yescarta), Wang noted.

Overall, 74 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.

"The efficacy, reliable and rapid manufacturing, and manageable toxicities identify an important and promising role for KTE-X19 in treating patients with relapsed/refractory mantle cell lymphoma who have an urgent unmet medical need," said Wang.

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, acalabrutinib, 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/m2plus cyclophosphamide at 500 mg/m2. KTE-X19 was administered at 2 x 106cells as a single infusion.

The median age of patients enrolled in the study 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%).

Prior to study entry, patients had received a median of 3 prior therapies, with that majority having 3 or more 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%).

"Bridging therapy was not intended to be curative, but simply to keep the lymphoma stable during manufacturing. The majority had increased tumor load instead of decreased tumor load," Wang said.

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.

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%).

"I have been treating mantle cell lymphoma for 20 years, and every time I see a plateau in the curve, I get very excited. But the follow-up is very short. We are still cautiously optimistic," said Wang.

As a single-arm study, Wang cited historical numbers for context. Overall, a typical ORR in patients with MCL who progress on BTK inhibition is 25% to 42%, he said. Additionally, few patients in this setting go on to receive potentially curative allogeneic stem cell transplant. The median OS for these patients is between 6 and 10 months. For the ZUMA-2 trial, at the 12.3-month analysis, the low end of the 95% CI for OS with KTE-X19 was 24 months.

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, siltuximab, 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.

"This is the first reported use of ATG in treating CAR T cell-related toxicities," said Wang. Anecdotally, he added that he had seen this patient recently, and that they remained in CR. Making the duration of response 30+ months.

In addition to the upcoming BLA submission, KTE-X19 has received a breakthrough therapy designation from the FDA and a prime medicines (PRIME) designation from the EMA, both based on findings from the ZUMA-2 trial.

Reference:

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.