CAR T-Cell Therapy (Yescarta) Receives FDA Approval for Second-Line Treatment of Large B-Cell Lymphoma

On April 1, 2022, the FDA (US Food and Drug Administration) approved the living cancer drug CAR T-cell therapy axicabtagene ciloleucel (Yescarta, Kite Pharma, Inc.) for adults with large B-cell lymphoma (LBCL) refractory to first-line chemoimmunotherapy or relapsing within the first 12 months—that is, before autologous bone marrow transplantation. This approval does not include patients with primary central nervous system lymphoma.

FDA Approval Based on the ZUMA-7 Study

The approval is based on ZUMA-7, a randomized, open-label, multicenter study in adults with primary refractory LBCL or relapse within 12 months after completing first-line treatment. Patients had not yet received treatment for relapsed or refractory lymphoma and were potential candidates for autologous hematopoietic stem cell transplantation.

A total of 359 patients achieving complete or partial remission after first-line treatment were randomized in a 1:1 ratio to receive a single axicabtagene ciloleucel infusion following fludarabine and cyclophosphamide lymphodepleting chemotherapy, or second-line standard treatment consisting of 2 or 3 cycles of chemoimmunotherapy followed by high-dose therapy and autologous stem cell transplantation. 

The primary efficacy measure was event-free survival (EFS), determined by an independent review committee.

• EFS was significantly longer in the axicabtagene ciloleucel arm, with a hazard ratio of 0.40 (95% CI: 0.31, 0.51; stratified p-value <0.0001).
• Estimated 18-month EFS 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-treatment arm.
• Estimated median EFS was 8.3 months (95% CI: 4.5, 15.8) and 2.0 months (95% CI: 1.6, 2.8), respectively.

Among patients randomized to standard treatment, 35% underwent autologous stem cell transplantation under the protocol; the most common reason for not undergoing transplantation was a lack of response to chemotherapy. The best objective response rate, assessed by an independent review committee, was statistically significantly higher in the axicabtagene ciloleucel arm than in the standard-treatment arm.

The prescribing information for axicabtagene ciloleucel contains a warning for cytokine release syndrome (CRS) and neurological toxicities. In axicabtagene ciloleucel studies in patients with non-Hodgkin lymphoma, CRS occurred in 90% (Grade ≥3, 9%) and neurological toxicities in 78% (Grade ≥3, 25%). The most common nonlaboratory adverse reactions (incidence ≥30%) were CRS, fever, hypotension, encephalopathy, fatigue, tachycardia, headache, nausea, febrile neutropenia, diarrhea, musculoskeletal pain, infections with an unidentified pathogen, chills, and decreased appetite.

The recommended dose of aksicabtagene ciloleucel is 2 x 1,000,000 chimeric antigen receptor CAR-positive viable T cells per kg of body weight; the maximum dose is 2 x 100,000,000.