Locke FL, et al. - Researchers present long-term activity and safety outcomes of the ZUMA-1 study, wherein, axicabtagene ciloleucel [an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] was tested as a treatment option for refractory large B-cell lymphoma. The previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7–17·3), reported an objective response in 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma, and complete responses in 63 (58%) patients. The ability of axicabtagene ciloleucel to induce durable responses and a median overall survival of greater than 2 years was demonstrated in 2-year follow-up data from ZUMA-1. Furthermore, it showed a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma.

Methods

• Including eligible patients, a single-arm, multicentre, registrational trial, named ZUMA-1, was conducted at 22 sites in the USA and Israel.
• Eligibility criteria included patients aged 18 years or older, having 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 having previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy.
• Following 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, researchers administered one dose of axicabtagene ciloleucel to participants on day 0 at a target dose of 2×10⁶ CAR T cells per kg of bodyweight.
• They focused on safety (primary endpoint for phase 1) and the proportion of patients achieving an objective response (primary endpoint for phase 2).
• They also evaluated overall survival, progression-free survival, and duration of response (key secondary endpoints).
• Based on the protocol, they performed pre-planned activity and safety analyses.

Results

• Enrollment of 119 patients and axicabtagene ciloleucel receipt by 108 across phases 1 and 2 was done between May 19, 2015, and Sept 15, 2016.
• As of the cutoff date of Aug 11, 2018, a median 27·1 months (IQR 25·7–28·8) follow-up was performed in 101 patients assessable for activity in phase 2, an objective response and a complete response was seen in 84 (83%) and 59 (58%) patients, respectively.
• The observed 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 of 5·9 months (95% CI 3·3–15·0) was observed.
• Grade 3 or worse serious adverse events were experienced by 52 (48%) of 108 patients assessable for safety in phases 1 and 2.
• Twelve (11%) patients experienced grade 3 or worse cytokine release syndrome, and 35 (32%) had grade 3 or worse neurological events.
• Since the previous analysis at 1 year, 4 patients were found to have additional serious adverse events (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 related.
• Previously, 2 treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were reported, but additional follow-up revealed no new treatment-related deaths.