First CAR T-cell therapy approvals bolster booming immunotherapy market

Approval followed positive results from the phase 2 single-arm, multicenter ZUMA-1 trial.⁶ Patients were included if they were aged 18 years of age and older, had histologically confirmed aggressive B-cell non-Hodgkin lymphoma that was chemotherapy refractory, had received adequate previous therapy, had at least 1 measurable lesion, had completed radiation or systemic therapy at least 2 weeks before, had resolved toxicities related to previous therapy, and had an Eastern Cooperative Oncology Group Performance Status of 0 (asymptomatic) or 1 (symptomatic), an absolute neutrophil count of ≥1000/µL, a platelet count of ≥50,000/µL, and adequate hepatic, renal and cardiac function. They were treated with a single infusion of axicabtagene ciloleucel after lymphodepleting chemotherapy.

Patients who had received previous CD19-targeted therapy, who had concomitant genetic syndromes associated with bone marrow failure, who had previous malignancy, and who had active or latent HBV/HCV infection were among those excluded from the study.

Patients were enrolled in 2 cohorts; those with DLBCL (n = 77) and those with PMBCL or transformed follicular lymphoma (n = 24). The primary endpoint was objective response rate, and after a primary analysis at a minimum of 6 months follow-up, the objective response rate was 82%, with a CR rate of 52%. Among patients who achieved CR, the median duration of response was not reached after a median follow-up of 7.9 months.

A subsequent updated analysis was performed when 108 patients had been followed for a minimum of 1 year. The objective response rate was 82%, and the CR rate was 58%, with some patients having CR in the absence of additional therapies as late as 15 months after treatment. At this updated analysis, 42% of patients continued to have a response, 40% of whom remained in CR.

The most common grade 3 or higher AEs included febrile neutropenia, fever, CRS, encephalopathy, infections, hypotension, and hypoxia. Serious AEs occurred in 52% of patients and included CRS, neurologic toxicity, prolonged cytopenias, and serious infections. Grade 3 or higher CRS or neurologic toxicities occurred in 13% and 28% of patients, respectively. Three patients died during treatment.

To mitigate the risk of CRS and neurologic toxicity, axicabtagene ciloleucel is approved with an REMS that requires appropriate certification and training before hospitals are cleared to administer the therapy.

Other warnings and precautions in the prescribing information relate to serious infections (monitor for signs and symptoms and treat appropriately), prolonged cytopenias (monitor blood counts), hypogammaglobulinemia (monitor immunoglobulin levels and manage appropriately), secondary malignancies (life-long monitoring), and the potential effects of neurologic events on a patient’s ability to drive and operate dangerous machinery (avoid for at least 8 weeks after infusion).⁷

Axicabtagene ciloleucel is marketed as Yescarta by Kite Pharma Inc. The recommended dose is a single intravenous infusion with a target of 2 x 10⁶ CAR-positive viable T cells per kilogram of body weight, preceded by fludarabine and cyclophosphamide lymphodepleting chemotherapy.