Primary Analysis of ZUMA-5: A Phase 2 Study of Axicabtagene Ciloleucel in Patients With Relapsed/Refractory Indolent Non-Hodgkin Lymphoma - Université de Lille Accéder directement au contenu
Article Dans Une Revue Blood Année : 2021

Primary Analysis of ZUMA-5: A Phase 2 Study of Axicabtagene Ciloleucel in Patients With Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

C. Jacobson
  • Fonction : Auteur
J. C. Chavez
  • Fonction : Auteur
A. R. Sehgal
  • Fonction : Auteur
B. M. William
  • Fonction : Auteur
J. Munoz
  • Fonction : Auteur
P. N. Munshi
  • Fonction : Auteur
C. Casulo
  • Fonction : Auteur
D. Maloney
  • Fonction : Auteur
S. de Vos
  • Fonction : Auteur
R. Reshef
  • Fonction : Auteur
L. A. Leslie
  • Fonction : Auteur
O. O. Oluwole
  • Fonction : Auteur
H. C. H. Fung
  • Fonction : Auteur
J. D. Rosenblatt
  • Fonction : Auteur
J. M. Rossi
  • Fonction : Auteur
L. Goyal
  • Fonction : Auteur
V. Plaks
  • Fonction : Auteur
Y. Yang
  • Fonction : Auteur
J. Lee
  • Fonction : Auteur
W. Godfrey
  • Fonction : Auteur
R. Vezan
  • Fonction : Auteur
M. P. Avanzi
  • Fonction : Auteur
S. S. Neelapu
  • Fonction : Auteur

Résumé

Background: Patients with advanced-stage iNHL, including follicular lymphoma (FL) and marginal zone lymphoma (MZL), frequently relapse with standard treatment, underscoring a need for novel therapies. Axi-cel autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy is approved for the treatment of R/R large B cell lymphoma after ≥ 2 lines of systemic therapy. Here, we present the primary analysis of ZUMA-5, a Phase 2, multicenter, single-arm study of axi-cel in patients with R/R iNHL. Methods: Adults with FL (Grades 1-3a) or MZL (nodal or extranodal) had R/R disease after ≥ 2 lines of therapy (must include an anti-CD20 mAb plus an alkylating agent), and ECOG 0 - 1. Patients underwent leukapheresis followed by conditioning therapy (cyclophosphamide/fludarabine) and a single infusion of axi-cel at 2 × 106 CAR T cells/kg. The primary endpoint was objective response rate (ORR) by central review (per Lugano classification; Cheson, et al. J Clin Oncol. 2014). Secondary endpoints included complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and levels of CAR T cells in blood and cytokines in serum. The primary efficacy analysis occurred when ≥ 80 treated patients with FL had ≥ 12-months follow-up. Results: As of 3/12/2020, 146 patients with iNHL (124 FL; 22 MZL) received axi-cel; 84 patients with FL had ≥ 12-months follow-up. The median age was 61 years (range, 34 - 79); 57% of patients were male. Thirty-eight percent of patients had ECOG 1, 86% had stage III/IV disease, 47% had ≥ 3 FLIPI, and 49% had high tumor bulk (GELF). Patients had a median 3 prior lines of therapy (range, 1 - 10); 64% had ≥ 3 prior lines. Progression < 2 years after initial chemoimmunotherapy (POD24) occurred in 55% of patients, and 68% were refractory to last prior treatment. Axi-cel was successfully manufactured for all enrolled patients. With a median follow-up of 17.5 months (range, 1.4 - 31.6), the ORR was 92% among efficacy-evaluable patients with iNHL (n = 104), with a 76% CR rate. In patients with FL (n = 84), the ORR was 94% (80% CR rate); in those with MZL (n = 20), the ORR was 85% (60% CR rate). ORR was comparable across key risk groups analyzed by FLIPI, POD24, GELF, refractory status, and prior lines of therapy. As of the data cutoff, 62% of all treated patients had ongoing responses (64% for FL). The medians for DOR, PFS, and OS were not reached; 12-month estimated rates were 72% (95% CI, 61 - 80), 74% (95% CI, 63 - 82), and 93% (95% CI, 86 - 97), respectively. AEs of any grade occurred in 99% of all treated patients. Grade ≥ 3 AEs occurred in 86% of patients with iNHL (85% in FL; 95% in MZL), most commonly neutropenia (33%), decreased neutrophil count (27%), and anemia (23%). Grade ≥ 3 cytokine release syndrome (CRS; per Lee, et al, Blood. 2014) occurred in 7% of patients with iNHL (6% in FL; 9% in MZL). Grade ≥ 3 neurologic events (NEs; per CTCAE v4.03) occurred in 19% of patients with iNHL (15% in FL; 41% in MZL). Most CRS (118/119) and NEs (81/87) of any grade resolved by data cutoff. Grade 5 AEs occurred in 3 patients: multisystem organ failure in the context of CRS (Day 7; related to axi-cel; n = 1 FL), aortic dissection (Day 399; unrelated to axi-cel; n = 1 FL), and coccidioidomycosis infection (Day 327; unrelated to axi-cel; n = 1 MZL). The median peak CAR T cell level was 38 cells/µL (range, 0 - 1415) in all treated patients with iNHL, with 36 cells/µL (range, 0 - 1415) in those with FL and 53 cells/µL (range, 2 - 453) in those with MZL. The AUC0 - 28 was 448 cells/µL × days (range, 6 - 19,900) in all treated patients with iNHL, with 422 cells/µL × days (range, 6 - 19,900) and 552 cells/µL × days (range, 13 - 6468) in those with FL and MZL, respectively. The median time to peak was 9 days (range, 8 - 371) in all patients, 8 days (range, 8 - 371) in patients with FL, and 15 days (range, 8 - 29) in patients with MZL. In efficacy-evaluable patients with FL, median peak CAR T cell levels were numerically greater in those with ongoing response at 12 months than in those who relapsed (P = .057). In all treated patients with FL, CAR T cell peak was associated with Grade ≥ 3 CRS (P = .031) and NEs (P = .005). Conclusions: Axi-cel had considerable and durable clinical benefit in patients with iNHL, with high ORR and CR rates. Axi-cel had a manageable safety profile, with lower rates of Grade ≥ 3 NEs observed in patients with FL vs those in patients with MZL and those previously reported in aggressive NHL (Locke, et al. Lancet Oncol. 2019).

Dates et versions

hal-04479419 , version 1 (27-02-2024)

Identifiants

Citer

C. Jacobson, J. C. Chavez, A. R. Sehgal, B. M. William, J. Munoz, et al.. Primary Analysis of ZUMA-5: A Phase 2 Study of Axicabtagene Ciloleucel in Patients With Relapsed/Refractory Indolent Non-Hodgkin Lymphoma. Blood, 2021, Blood, 19, ⟨10.1182/blood-2020-136834⟩. ⟨hal-04479419⟩
10 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More