1. Patients with large B-cell lymphoma refractory to first-line therapy receiving axicabtagene ciloleucel (axi-cel) showed improvement in event-free survival compared to patients receiving standard care.

2. Axi-cel was associated with high-grade adverse side effects including cytokine release syndrome and neurologic events.

Evidence Rating Level: 1 (Excellent)  

Study Rundown: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for third-line use in refractory large B-cell lymphoma. To investigate its efficacy as a second-line agent, the ZUMA-7 randomized controlled trial enrolled patients with large B-cell lymphoma that did not respond to first-line chemoimmunotherapy within 12 months to either receive axi-cel or standard salvage therapy consisting of high-dose chemotherapy and autologous stem-cell transplantation. The primary outcomes for this study analyzed event-free and overall survival. Adverse events were assessed as a secondary outcome. The study found that patients receiving second-line axi-cel demonstrated a higher proportion of therapy response, which corresponded to a significantly longer median event-free survival than patients receiving standard therapy. However, axi-cel was also associated with a higher rate of severe adverse events with its patients experiencing cytokine release syndrome and neurologic events, although no associated deaths were reported. Overall, this study supports the use of axi-cel as an alternative second-line therapy for refractory patients with large B-cell lymphoma. While therapeutic efficacy was demonstrated, the study warns of limitations such as a lack of analysis on biological factors influencing responses to CAR-T cell therapy and whether all patients in this population would benefit. Moreover, this study did not enroll patients who were refractory or relapsed more than 12 months from receiving initial therapy.

Click to read the study in NEJM 

Relevant Reading: Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial

In-Depth [randomized controlled trial]: In this international, multi-center, randomized control trial, the ZUMA-7 trial aimed to investigate the efficacy of axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, as a second-line treatment. 180 patients with large B-cell lymphoma with the refractory or relapsed disease to first-line chemoimmunotherapy within 12 months in patients with large B-cell lymphoma were randomized in a 1:1 ratio to receive conditioning chemotherapy with a single infusion of axi-cel or standard salvage chemoimmunotherapy at the investigator’s discretion including an opportunity for autologous stem-cell transplantation. The primary endpoint was event-free survival as determined by blinded-central review, which was analyzed using Kaplan-Meier estimates and Cox proportional-hazards models with stratification. Secondary endpoints were progress-free survival, the incidence of adverse events, and treatment kinetics. The results of the study demonstrated that patients receiving axi-cel experienced longer event-free survival times with a median of 8.3 months compared to the control group at 2.0 months (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.31-0.51; P<0.001). Corresponding estimated event-free survival rates after 2 years were also favorable for the experimental group at 41% vs. 16% in the control. Patients receiving axi-cel demonstrated 1.66 times the percentage of response to therapy. With respect to safety, all patients experienced at last one adverse, but proportions of severe adverse event incidence were comparable between the axi-cel and control groups (91 vs. 83%). 92% of patients receiving axi-cel experienced cytokine release syndrome and 60% experienced a neurologic event; however, no deaths occurred due to these adverse events. Finally, measured plasma CAR-T levels found that levels peak 7 days post-infusion and were detectable in 40% of treated patients after 2 years. Altogether, this study supports the use of axi-cel as second-line therapy following relapse or refractory disease in patients with large-cell lymphoma.

Image: PD

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