EMA Review of Axicabtagene Ciloleucel (Yescarta) for the Treatment of Diffuse Large B‐Cell Lymphoma

On June 28, 2018, the Committee for Advanced Therapies and the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Yescarta for the treatment of adult patients with relapsed or refractory diffuse large B‐cell lymphoma and primary mediastinal large B‐cell lymphoma, after two or more lines of systemic therapy. Yescarta, which was designated as an orphan medicinal product and included in the European Medicines Agency's Priority Medicines scheme, was granted an accelerated review timetable. The active substance of Yescarta is axicabtagene ciloleucel, an engineered autologous T‐cell immunotherapy product whereby a patient's own T cells are harvested and genetically modified ex vivo by retroviral transduction using a retroviral vector to express a chimeric antigen receptor (CAR) comprising an anti‐CD19 single chain variable fragment linked to CD28 costimulatory domain and CD3‐zeta signaling domain. The transduced anti‐CD19 CAR T cells are expanded ex vivo and infused back into the patient, where they can recognize and eliminate CD19‐expressing cells. The benefits of Yescarta as studied in ZUMA‐1 phase II (NCT02348216) were an overall response rate per central review of 66% (95% confidence interval, 56%–75%) at a median follow‐up of 15.1 months in the intention to treat population and a complete response rate of 47% with a significant duration. The most common adverse events were cytokine release syndrome, neurological adverse events, infections, pyrexia, diarrhea, nausea, hypotension, and fatigue. Implications for Practice Yescarta (axicabtagene ciloleucel) was the first chimeric antigen receptor T‐cell therapy to be submitted for evaluation to the European Medicines Agency and admitted into the “priority medicine” scheme; it was granted accelerated assessment on the basis of anticipated clinical benefit in relapsed/refractory diffuse large B‐cell lymphoma, a condition of unmet medical need. Indeed, Yescarta showed an overall response rate of 66% and a complete response rate of 47% with a significant duration and a manageable toxicity that compared very favorably with historical controls. Here the analysis of benefits and risks is presented, and specific challenges with this important novel product are highlighted, providing further insights and reflections for future medical research. This article summarizes the data leading to marketing authorization for the