On 1 April 2022, the US Food and Drug Administration (FDA) approved axicabtagene ciloleucel (Yescarta, Kite Pharma, Inc.) for adult patients with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy. It is not indicated for the treatment of patients with primary central nervous system lymphoma.
Approval was based on ZUMA-7, a randomised, open-label, multicentre study in adult patients with primary refractory LBCL or relapse within 12 months following completion of first-line therapy. Patients had not yet received treatment for relapsed or refractory lymphoma and were potential candidates for autologous haematopoietic stem cell transplantation (HSCT). A total of 359 patients were randomised 1:1 to receive a single infusion of axicabtagene ciloleucel following fludarabine and cyclophosphamide lymphodepleting chemotherapy or to receive second-line standard therapy, consisting of 2 or 3 cycles of chemoimmunotherapy followed by high-dose therapy and autologous HSCT in patients who attained complete remission or partial remission.
The primary efficacy measure was event-free survival (EFS) determined by an independent review committee (IRC). EFS was significantly longer in the axicabtagene ciloleucel arm with a hazard ratio of 0.40 (95% confidence interval [CI] 0.31, 0.51; stratified p-value <0.0001). The estimated 18-month EFS rate was 41.5% (95% CI 34.2, 48.6) in the axicabtagene ciloleucel arm and 17.0% (95% CI 11.8, 23.0) in the standard therapy arm. The estimated median EFS was 8.3 months (95% CI 4.5, 15.8) and 2.0 months (95% CI 1.6, 2.8), respectively. Of patients randomised to receive standard therapy, 35% received on-protocol autologous HSCT; lack of response to chemotherapy was the most common reason for not receiving HSCT. The IRC-assessed best objective response rate was statistically significantly higher in the axicabtagene ciloleucel arm compared to the standard therapy arm: 83% (95% CI 77, 88) vs. 50% (95% CI 43, 58), respectively.
The prescribing information for axicabtagene ciloleucel has a boxed warning for cytokine release syndrome (CRS) and neurologic toxicities. In studies of axicabtagene ciloleucel in patients with non-Hodgkin lymphoma, CRS occurred in 90% (Grade ≥3, 9%) and neurologic toxicities occurred in 78% (Grade ≥3, 25%). The most common non-laboratory adverse reactions (incidence ≥30%) are CRS, fever, hypotension, encephalopathy, fatigue, tachycardia, headache, nausea, febrile neutropenia, diarrhoea, musculoskeletal pain, infections with pathogen unspecified, chills, and decreased appetite.
The recommended axicabtagene ciloleucel dose is 2 x 106 chimeric antigen receptor (CAR)-positive viable T cells per kg of body weight, with a maximum of 2 x 108 CAR-positive viable T cells.
Full prescribing information for Yescarta is available here.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted priority review, breakthrough therapy designation, and orphan drug designation.
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