5-Year Follow-Up Supports Curative Potential of Axicabtagene Ciloleucel in Refractory Large B-Cell Lymphoma (ZUMA-1)

Abstract

In phase 2 of ZUMA-1, a single-arm, multicenter, registrational trial, axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL). Here, we aimed to assess survival and safety in ZUMA-1 after 5 years of follow-up. Eligible adults with refractory LBCL (diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma) received lymphodepleting chemotherapy followed by axi-cel infusion targeted at 2×106 cells/kg. Investigator-assessed response, updated survival, safety, and pharmacokinetic outcomes were assessed in treated patients. The objective response rate in the 101 treated patients was 83% (58% complete response rate), and with a median follow-up of 63.1 months, responses were ongoing at data cutoff in 31%. Median overall survival (OS) was 25.8 months and the estimated 5-year OS rate was 42.6%. Disease-specific survival (excluding deaths unrelated to disease progression) estimated at 5 years was 51.0%. No new serious adverse events or deaths related to axi-cel were observed after additional follow-up. Peripheral blood B cells were detectable in all evaluable patients at 3 years with polyclonal B-cell recovery in 91%. Ongoing responses at 60 months were associated with early CAR T-cell expansion. In conclusion, this 5-year follow-up analysis of ZUMA-1 demonstrates sustained overall and disease-specific survival, with no new safety signals in patients with refractory LBCL. Protracted B-cell aplasia was not required for durable responses. These findings support the curative potential of axi-cel in a subset of patients with aggressive B-cell lymphomas. ClinicalTrials.gov, number NCT02348216

CAR T‐cell therapy in large B cell lymphoma

“…3 As of August 2021, 30% of patients had ongoing CR with a median duration of CR of 62.2 months, highlighting ongoing durability of response and the curative potential of this form of therapy. 4 Importantly, results from subsequent real-world analyses were consistent with phase 2 safety and efficacy data. 11,12,[14][15][16][17][18] For example, a retrospective study of standard of care (SOC) axi-cel from the US lymphoma consortium included 275 patients, 43% of which would not have met ZUMA-1 eligibility criteria due to medical comorbities.…”

“…On long‐term follow‐up, the overall 5‐year OS rate was 42.6% (95% CI, 32.8–51.9), while complete responders fared better at 64.4% (95% CI: 50.8–75.1) 3 . As of August 2021, 30% of patients had ongoing CR with a median duration of CR of 62.2 months, highlighting ongoing durability of response and the curative potential of this form of therapy 4 . Importantly, results from subsequent real‐world analyses were consistent with phase 2 safety and efficacy data 11,12,14–18 .…”

“…1 Since then, several of these products have led to impressive response rates and durable remissions in the treatment of relapsed or refractory aggressive non-Hodgkin lymphoma (NHL), including large B cell lymphoma (LBCL). [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Axicabtagene ciloleucel (axi-cel; KTE-C19) is an autologous CD19-CAR T-cell product bearing a CD28 costimulatory domain. In the pivotal single-arm phase 2, multicenter ZUMA-1 trial, 101 patients with relapsed or refractory (r/r) LBCL after two or more lines of therapy were treated with a single infusion of axi-cel.…”

“…Second generation CD19‐CAR T‐cells bearing a crucial costimulatory molecule first demonstrated pre‐clinical efficacy in hematologic malignancies in 2003 1 . Since then, several of these products have led to impressive response rates and durable remissions in the treatment of relapsed or refractory aggressive non‐Hodgkin lymphoma (NHL), including large B cell lymphoma (LBCL) 2–18 . Axicabtagene ciloleucel (axi‐cel; KTE‐C19) is an autologous CD19‐CAR T‐cell product bearing a CD28 costimulatory domain.…”

Challenges and solutions to superior chimeric antigen receptor‐T design and deployment for B‐cell lymphomas

“…9 Ongoing responses at the 5-year mark from ZUMA-1 have been associated with expansion of CAR-T cells. 9 This attests to the sustainability of CAR-T therapies. The model of using CAR-T therapy as a bridge to stem cell transplant may be replaced by CAR-T as destination therapy if long-term data lends support to this.…”