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

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 NCT02348216. 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 related. Two treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were previously reported, but no new treatment-related deaths occurred during the additional follow-up.

Interpretation: These 2-year follow-up data from ZUMA-1 suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma.

Funding: Kite and the Leukemia & Lymphoma Society Therapy Acceleration Program.

Conflict of interest statement

Declaration of interests

FLL has served on scientific advisory boards for Kite and Novartis and reports consultancy fees for Cellular Biomedicine and research support from Forma Therapeutics. AGh has received speaker fees and research funding from, and served on scientific advisory boards for, Kite. CAJ reports personal fees from Kite, Novartis, Precision Bioscience, Bayer, Pfizer, and Humanigen. DBM has received grants and research funding from, and served on scientific advisory boards for, Kite. IB reports speaker fees from Kite. BTH has served on advisory boards for Gilead. AD has served on advisory boards for Kite, Agios, and Novarits, and received research funding from Bristol-Myers Squibb. PMR reports research funding from Seattle Genetics, and has served on advisory boards for, and received personal fees from, Curis. IWF reports research funding from Kite, Agios, ArQule, Beigene, Calithera, Celgene, Constellation, Curis, Forma, Forty-Seven, Genentech, Gilead, Incyte, Infinity, Janssen, Merck, Novartis, Pfizer, Pharmacyclics, Portola, Seattle Genetics, Takeda, TG Therapeutics, Trillium, Verastem, and Roche. UF reports travel support from Kite and honoraria from Celgene. AGo has participated in speakers bureaus for, and received research funding from, Takeda, Kite, Gilead, Pharmacyclics, Janssen, Genentech, and Acerta, and has a leadership role at COTA, a for-profit health-care company. PAM reports speaker and consultant fees from Kite. JM has participated on speakers bureaus or advisory boards for Kite, Pharmacyclics, Janssen, Bayer, Alexion, Pfizer, Juno, Celgene, Bristol-Myers Squibb, Genentech, and Kyowa. TS reports travel support from Kite, speaker and consultancy fees from Pharmacyclics; speaker fees from Janssen and Seattle Genetics, and consultancy for Juno and BeiGene. JCC has participated in advisory boards or speakers bureaus for Kite, Genentech, Novartis, Bayer, and Janssen, and has received research support from Merck. AFH reports grants, personal fees, and consultancy for Bristol-Myers Squibb, Genentech, Merck, Pharamcyclics, and Kite, and grants and consultancy for Gilead. NLB reports research funding from Affimed, Bristol-Meyers Squibb, Celgene, Forty Seven, Genentech, Gilead, Immune Design, Kite, Merck, Millennium, Pharmacyclics, and Acerta, and has served on advisory boards for Pfizer. LN, JMR, AX, YJ, JJK, and WYG, are employed by Kite, and have equity ownership in Gilead. AB and JSW report employment and an issued patent with Kite. SSN reports personal fees and research support from Kite, Merck, and Celgene, research support from Bristol-Myers Sqibb, Poseida, Cellectis, Karus, and Acerta Pharma, and personal fees from Novartis, Pfizer, and Unum Therapeutics. LJL, OOO, YL, JMT, and PS declare no competing interests.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. Kaplan-Meier estimates of investigator-assessed duration of response (A), progression-free survival (B), and overall survival (C)

All 101 patients assessable for activity in phase 2 are shown. The x-axis shows time since infusion of chimeric antigen receptor T cells. NE=not estimable.

Figure 2:. Post-hoc analysis of investigator-assessed progression-free survival by response status at 3 months after axicabtagene ciloleucel

60 patients with ongoing complete response, partial response, or stable disease month 3 in phase 2 are shown. The x-axis shows time since infusion of chimeric antigen receptor T cells. Four of eight patients with partial responses and four of nine patients with stable disease at 3 months subsequently converted to complete responses. NR=not reached. NE=not estimable.

Figure 3:. Post-hoc analysis of CAR T-cell and B-cell concentrations

CAR T cell exposure by peak concentrations of CAR T cells in peripheral blood (A) or area under the curve (B) and proportion of patients with responses at 24 months with detectable B cells (C). For (A) and (B), the horizontal line within each box represents the median, the lower and upper borders of each box represent the IQR, and the bars show the range. CAR area under the curve is defined as cumulative concentrations of CAR gene-marked cells per μL of blood during the first 28 days after axicabtagene ciloleucel therapy. For (A) and (B), these analyses include all 101 phase 2 patients assessable for activity with the exception of two patients who received subsequent anticancer therapy while in response to axicabtagene ciloleucel, two patients who died before disease progression, and two patients for whom CAR T-cell data were not available. For (C), this analysis includes patients in ongoing response with assessable samples and excludes two patients who received subsequent anticancer therapy while in response to axicabtagene ciloleucel. CAR=chimeric antigen receptor. N/A=not applicable.