The previous phase III ZUMA-7 trial demonstrated that second-line treatment with axicabtagene ciloleucel (axi-cel), an autologous CD19-targeting chimeric antigen receptor (CAR) T-cell therapy, was superior to standard therapy consisting of platinum-based chemotherapy followed by high-dose chemotherapy and autologous stem-cell transplantation (HDT-ASCT) (hazard ratio [HR] = 0.40; p<0.001 in stratified log-rank test) in improving the primary outcome of event-free survival (EFS) in patients with early-relapse large B-cell lymphoma (LBCL).1 Based on this finding, the Food and Drug Administration (FDA) approved axi-cel as a second-line treatment in patients with primary refractory LBCL or relapsed disease within 12 months following completion of firstline therapy in April 2022. However, whether these benefits in EFS translate to improvements in overall survival (OS) remained to be determined given the immaturity of the OS data and that CAR T-cell therapy is an approved third-line treatment.
In their recent work, Dr. Jason Westin and colleagues report the primary OS analysis after a protocol-defined interval.2 At a median follow up of 47.2 months (range: 39.8 to 60.0 months), the OS rate was significantly higher for the axi-cel group than for the standard-of-care group (HR for death: 0.73; 95% CI 0.54-0.98; p=0.03). The median OS was not reached (95% CI 28.6 months to not estimable) with axi-cel and was 31.1 months (95% CI 17.1 to not estimable) with the standard of care. High-risk features were balanced in the treatment arms. Importantly, in the standard-of-care group, 80% of patients who experienced disease progression or lack of response underwent subsequent standard-of-care third-line CAR T-cell therapy. An exploratory analysis revealed that peak and area under the curve (AUC) values for CAR T-cell levels within the first 28 days after infusion were not significantly associated with OS. In the axi-cel group, the OS benefit was associated with a greater proportion of T-cells bearing stem memory phenotypes and a lower proportion bearing effector memory phenotype.
In Brief
This work emphasizes the revolutionary improvements in OS among patients with LBCL that we have achieved using CAR T-cell therapy over the past five years. Importantly, given that 80% of patients randomized to the standard-of-care arm received subsequent CAR T-cell therapy, the work of Dr. Westin and colleagues addresses concerns about the robustness of the benefit provided by second-line axi-cel. Moreover, their results add to the growing body of literature indicating that relatively earlier delivery of CAR T-cell therapy may be more effective given that T-cell function may be better in earlier stages of disease.3,4 Due to the compelling OS advantage, we anticipate CAR T-cell therapy will be the preferred second-line approach for LBCL. However, will supply be able to keep up with demand? To ensure health equity, we must improve access, encourage early referral to certified treating centers, and scale up manufacturing. Expanding the availability of CAR T-cell therapy in real-world settings is critical for ensuring that more patients have access to these benefits.
Competing Interests
Dr. McCurry indicated no relevant conflicts of interest. Dr. Nastoupil has received honoraria and research support from BMS, Gilead/Kite, Janssen, and Novartis.
