On April 1, 2022, the U.S. Food and Drug Administration (FDA) approved axicabtagene ciloleucel (Yescarta®) 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.

FDA Approves Axicabtagene Ciloleucel for Second-Line Treatment of Large B-Cell Lymphoma

Approval was based on the results of a randomized, open-label, multicenter trial (ZUMA-7) that evaluated 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 hematopoietic stem cell transplantation (HSCT). A total of 359 patients were randomized 1:1 to receive a single infusion of axicabtagene ciloleucel following fludarabine and cyclophosphamide lymphodepleting chemotherapy or to receive standard second-line therapy (i.e., two or three cycles of chemoimmunotherapy followed by high-dose therapy and autologous HSCT for patients who attained complete 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% CI = 0.31, 0.51; stratified p < 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 the patients randomized 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) versus 50% (95% CI = 43, 58), respectively.

Axicabtagene ciloleucel’s prescribing information 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 reported in 30% or more of patients are CRS, fever, hypotension, encephalopathy, fatigue, tachycardia, headache, nausea, febrile neutropenia, diarrhea, musculoskeletal pain, infections with unspecified pathogens, 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.

View the full prescribing information for axicabtagene ciloleucel.

The review used the Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment.

The application was granted priority review, breakthrough therapy designation, and orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry—Expedited Programs for Serious Conditions—Drugs and Biologics.

Healthcare professionals should report all serious adverse events they suspect are associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.

For assistance with single-patient investigational new drug applications for oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.