Background
Phase II ZUMA-1 enrolled 111 patients with relapsed/refractory DLBCL, PMBCL, or transformed FL to receive axicabtagene ciloleucel (axi-cel) on day 0 after fludarabine (30 mg/m2) + cyclophosphamide (500 mg/m2) conditioning on days −5 to −3. No bridging therapy was permitted after leukapheresis.
Interventions and follow up
Regimen: Axi-cel at target dose 2 x 10^6 anti-CD19 CAR-T cells/kg, single infusion, after Flu/Cy lymphodepletion.
Histology: 77 DLBCL, 8 PMBCL, 16 transformed FL.
Primary endpoint: Objective response rate (ORR).
mFollow up: 15.4 months.
Histology: 77 DLBCL, 8 PMBCL, 16 transformed FL.
Primary endpoint: Objective response rate (ORR).
mFollow up: 15.4 months.
Results
Population: median age 58 (23-76), 67% male, 85% stage III/IV, 48% IPI 3-4; 69% had ≥3 prior lines; 77% refractory to 2nd-line, 21% relapsed post auto-HCT.
ORR: 82% (CR 54%).
Median time to response: 1 month (0.8-6).
Median DoR: 11.1 months.
mPFS: 5.8 months (95% CI 3.3 to NE).
mOS: not reached (95% CI 12 to NE).
6/12/18-mo OS: 78% / 59% / 52%.
ORR: 82% (CR 54%).
Median time to response: 1 month (0.8-6).
Median DoR: 11.1 months.
mPFS: 5.8 months (95% CI 3.3 to NE).
mOS: not reached (95% CI 12 to NE).
6/12/18-mo OS: 78% / 59% / 52%.
Adverse events
CRS (Lee/CTCAE): 93% any grade, 13% grade ≥3; median onset 2 days.
Neurotoxicity (CTCAE): 64% any grade, 28% grade ≥3; median onset 5 days.
Hematologic/other: grade ≥3 cytopenias were common; serious infections occurred; there were treatment-related deaths reported.
Neurotoxicity (CTCAE): 64% any grade, 28% grade ≥3; median onset 5 days.
Hematologic/other: grade ≥3 cytopenias were common; serious infections occurred; there were treatment-related deaths reported.
Conclusions
Axi-cel produces high response rates in R/R LBCL (ORR 82%, CR 54%) with durable remissions (median DoR 11.1 mo, 18-mo OS 52%), at the cost of frequent CRS and neurotoxicity.
Key Limitations
Single-arm phase II without a comparator; no bridging therapy allowed, limiting generalizability to patients with rapidly progressive disease. High-grade CRS and neurotoxicity require management at experienced centers, and longer follow-up was needed to define cure fraction.
Clinical Context
ZUMA-1 led to FDA approval (2017) of axi-cel for R/R LBCL after ≥2 prior lines, establishing CD19 CAR-T as standard third-line therapy per ASCO/ESMO guidance. ZUMA-7 later moved axi-cel into the second-line setting for early relapse.
References