As reported in The New England Journal of Medicine by Frederick L. Locke, MD, of the Department of Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, Florida, and colleagues, the phase III ZUMA-7 trial in large B-cell lymphoma has shown improved event-free survival with second-line axicabtagene ciloleucel vs standard-of-care chemoimmunotherapy with high-dose chemotherapy and autologous stem cell transplantation (SCT) in chemoimmunotherapy responders.¹

Frederick L. Locke, MD

Study Details

In the trial, 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, were randomly assigned between January 2018 and October 2019 to axicabtagene ciloleucel (n = 180) or standard care (n = 179). Randomization was stratified according to response to first-line therapy and second-line age-adjusted International Prognostic Index risk factors.

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 chimeric antigen receptor T cells/kg. Patients in the standard-of-care group received two to three cycles of protocol-defined investigator-selected platinum-based chemoimmunotherapy; those with a complete or partial response proceeded to high-dose chemotherapy with autologous SCT.

Common regimens used in the standard-of-care group included  rituximab plus gemcitabine, dexamethasone, and cisplatin/carboplatin; rituximab plus dexamethasone, high-dose cytarabine, and cisplatin; rituximab plus ifosfamide, carboplatin, and etoposide; and rituximab plus etoposide, methylprednisolone, cytarabine, and cisplatin.

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-of-care group, 168 patients (94%) received platinum-based salvage chemoimmunotherapy and 64 (36%) received high-dose chemotherapy and underwent autologous SCT.

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-of-care group (hazard ratio [HR] = 0.40, 95% CI = 0.31–0.51, P < .001), with estimated 24-month rates of 41% (95% CI = 33%–48%) vs 16% (95% CI = 11%–22%). 

In stratification subgroups, hazard ratios were 0.43 (95% CI = 0.32–0.57) among 264 patients with primary refractory disease as a response to first-line therapy and 0.34 (95% CI = 0.20–0.58) among 95 who relapsed ≤ 12 months after initiation or completion of first-line therapy, and 0.41 (95% CI = 0.28–0.58) among 198 patients with 0 or 1 second-line age-adjusted International Prognostic Index risk factors and 0.39 (95% CI = 0.27–0.56) among 161 with 2 or 3 risk factors.

An objective response occurred in 83% vs 50% of patients (P < .001), with a complete response in 65% vs 32%. Median progression-free survival was 14.7 months (95% CI = 5.4 months to not estimable) in the axicabtagene ciloleucel group vs 3.7 months (95% CI = 2.9–5.3 months) in the standard-of-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 to not estimable) in the axicabtagene ciloleucel group vs 35.1 months (95% CI = 18.5 months to not estimable) in the standard-of-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 the standard-of-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 the axicabtagene ciloleucel group vs 83% of the standard-of-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-of-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. Prolonged grade ≥ 3 cytopenias present at ≥ 30 days after receipt of axicabtagene ciloleucel infusion or first dose of high-dose chemotherapy were observed in 29% of patients who received axicabtagene ciloleucel and in 12 (19%) of 62 patients in the standard-of-care group who underwent autologous SCT.

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-of-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.” 

DISCLOSURE: The study was funded by Kite. Dr. Locke has served as consultant or advisor to Allogene, American Society of Hematology, Amgen, Aptitude Health, Biopharma Communications, Bluebird Bio, Bristol Myers Squibb, Calibr, CARE Education, Celgene, Cellular Biomedicine Group, Clinical Care Options, Cowen, EcoR1, Emerging Therapy Solutions, Gamma Delta Therapeutics, Gerson Lehrman Group, Gilead Sciences, Iovance, Janssen Biotech, Kite Pharma, Legend Biotech, Novartis, Sana Biotechnology, Society for Immunotherapy of Cancer, Takeda, Umoja, and Wugen; has received research funding from Bluebird Bio, Kite Pharma, and Leukemia and Lymphoma Society; has stock options in Cellular Biomedicine Group; has been reimbursed for travel by Gilead Sciences; and has institutional patents on CAR T-cell– and vaccine-related therapies. 

REFERENCE

1. Locke FL, Miklos DB, Jacobson CA, et al: Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med 386:640-654, 2022.