As reported in The New England Journal of Medicine by Frederick L. Locke, MD, and colleagues, the phase III ZUMA-7 trial of patients with large B-cell lymphoma has shown improved event-free survival with second-line axicabtagene ciloleucel vs chemoimmunotherapy with high-dose chemotherapy and autologous stem cell transplantation in chemoimmunotherapy responders.

Frederick L. Locke, MD

Study Details

The trial included 359 patients from 77 sites worldwide with disease that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy including an anti-CD20 monoclonal antibody and anthracycline-containing regimen. Patients were randomly assigned between January 2018 and October 2019 to receive axicabtagene ciloleucel (n = 180) or standard care (n = 179). Patients in the axicabtagene ciloleucel group underwent leukapheresis followed by conditioning chemotherapy with cyclophosphamide and fludarabine at −5, −4, and −3 days before receiving a single infusion of axicabtagene ciloleucel at a target dose of 2 × 10⁶ CAR T cells/kg. Patients in the standard care group received two or three cycles of protocol-defined investigator-selected platinum-based chemoimmunotherapy; those with complete or partial response proceeded to high-dose chemotherapy with autologous stem cell transplant. The primary endpoint was event-free survival on blinded central review in the intention-to-treat population.

Event-Free Survival

Among patients in the axicabtagene ciloleucel group, 178 (99%) underwent leukapheresis and 170 (94%) received axicabtagene ciloleucel; 65 (36%) received bridging therapy with glucocorticoids. In the standard-care group, 168 patients (94%) received platinum-based salvage chemoimmunotherapy and 64 (36%) received high-dose chemotherapy and underwent autologous stem cell transplant.

Median follow-up was 24.9 months. Median event-free survival was 8.3 months (95% confidence interval [CI] = 4.5–15.8 months) in the axicabtagene ciloleucel group vs 2.0 months (95% CI = 1.6–2.8 months) in the standard-care group (hazard ratio [HR] = 0.40, 95% CI = 0.31­0.51, P < .001), with estimated 24-month rates of 41% (95% CI = 33%–48%) vs 16% (95% CI = 11%–22%).

Objective response occurred in 83% vs 50% of patients (P < .001), with complete response in 65% vs 32%. Median progression-free survival was 14.7 months (95% CI = 5.4 months–not estimable) in the axicabtagene ciloleucel group vs 3.7 months (95% CI = 2.9–5.3 months) in the standard-care group (HR = 0.49, 95% CI = 0.37–0.65), with estimated 24-month rates of 46% (95% CI = 38%–53%) vs 27% (95% CI = 20%–35%).

On interim analysis, median overall survival was not reached (95% CI = 28.3 months–not estimable) in the axicabtagene ciloleucel group vs 35.1 months (95% CI = 18.5 months–not estimable) in the standard-care group (HR = 0.73, 95% CI = 0.53–1.01, P = .054), with estimated 24-month rates of 61% vs 52%. A total of 56% of patients in the standard-care group received subsequent cellular immunotherapy; a prespecified sensitivity analysis to account for the effect of the treatment switching showed a hazard ratio of 0.58 (95% CI = 0.42–0.81).

Adverse Events

Grade ≥ 3 adverse events occurred in 91% of patients in the axicabtagene ciloleucel group vs 83% of the standard-care group. The most common were neutropenia (69%), anemia (30%), and leukopenia in the axicabtagene ciloleucel group, and thrombocytopenia (57%), neutropenia (41%), and anemia (39%) in the standard-care group. Any-grade cytokine-release syndrome and neurologic adverse events occurred in 92% and 60%, respectively, of the axicabtagene ciloleucel group and were grade ≥ 3 in 6% and 21%; no deaths related to cytokine-release syndrome or neurologic events were observed. Serious adverse events occurred in 50% vs 46% of patients. Infections of any grade occurred in 41% vs 30% and were grade ≥ 3 in 14% vs 11%. Fatal adverse events occurred in seven patients (4%) in the axicabtagene ciloleucel group, with one (hepatitis B virus reactivation) considered related to treatment. Fatal adverse events occurred in two patients (1%) in the standard-care group, with both (cardiac arrest and acute respiratory distress syndrome) considered related to high-dose chemotherapy.

The investigators concluded, “Axicabtagene ciloleucel therapy led to significant improvements, as compared with standard care, in event-free survival and response, with the expected level of high-grade toxic effects.”

Dr. Locke, of the Department of Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by Kite. For full disclosures of the study authors, visit nejm.org.