Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial

Abstract

Summary Background Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7–17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study. Methods ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B-cell lymphoma—including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma—according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2 × 106 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m2 body-surface area) and cyclophosphamide (500 mg/m2 body-surface area) on days −5, −4, and −3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre-planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov, number . Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway. Findings Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27·1 months (IQR 25·7–28·8), 84 (83%) had an objective response, and 59 (58%) had a complete response. The median duration of response was 11·1 months (4·2–not estimable). The median overall survival was not reached (12·8–not estimable), and the median progression-free survival was 5·9 months (95% CI 3·3–15·0). 52 (48%) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients, and grade 3 or worse neurological events in 35 (32%). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment r...

Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations

“…However, preclinical models and exploratory comparisons between single-arm clinical studies suggest CAR T cells incorporating each of these domains may differ qualitatively. 69 In contrast, in B-ALL, a malignancy of precursor B cells, 41BB-costimulated CAR T cells may elicit numerically longer median progression-free survival rates, 38,70 and a loss of CAR T cell persistence often heralds relapse. 27 Consistent with this, pharmacokinetic analyses of The second-generation CAR T cell trials in 'other' include 2 trials where an admix of second-generation CARs containing 41BB and CD28 was administered, and two trials where either 41BB or CD28 containing second-generation CARs were administered.…”

Cellular therapy: Immune‐related complications

“…Abxicabtagene ciloleucel, marketed as Yescarta (Gilead), is an FDA approved CD‐19 directed CAR‐T with a CD28 costimulatory domain that showed similarly excellent results in relapsed/refractory adult Non‐Hodgkin's Lymphomas (NHL) . In the most recent update of the Zuma‐1 trial, there was an overall survival of 51% with a CR of 39% in patients with large B‐cell lymphomas at a median of 2 years follow‐up from infusion . Similar excellent results were recently published with tisagenlecleucel in adult relapsed or refractory diffuse large B‐cell lymphoma …”

“…Cytokine Release Syndrome is a known side effect of all current CD‐19 directed CAR‐T therapies and has occurred in patients with B‐ALL, DLCBL and CLL . The onset of CRS is directly related to the properties of the co‐stimulatory molecules incorporated in the CAR‐T construct.…”

“…In comparison to 4‐IBB, the inclusion of a CD28 costimulatory domain promotes rapid and immediate CAR‐T proliferation with a shortened persistence. In patients with NHL treated with abxicabtagene ciloleucel the median onset from time of infusion to beginning of CRS was a median of 2 days (range: 1‐12 days) and to resolution was a median of 7 days (range: 2‐58 days) . The onset of CRS is also dependent on receptor‐antigen interaction and the downstream signal transduction from the chimeric TCR.…”

CAR T cells for brain tumors: Lessons learned and road ahead

“…CD19‐CAR T clinical experiences have also provided points of caution for neurotoxicity that can be associated with CAR T cells. The incidence of high‐grade neurotoxicity occurs in approximately 12%‐32% of patients treated with CD19‐CARs across indications, and includes symptoms of delirium, confusion, and seizures . Lethal cerebral edema has also been reported in a handful of patients treated with CD19‐CAR T cells in B‐ALL and non‐Hodgkin's lymphoma, highlighting the life‐threatening risks of immune inflammatory reactions in the CNS.…”