On June 24, the U.S. Food and Drug Administration (FDA) approved the chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (Breyanzi) for adult patients with large B-cell lymphoma (LBCL) who have disease refractory to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or disease refractory to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age. It is not indicated for the treatment of patients with primary central nervous system lymphoma.
Efficacy was evaluated in TRANSFORM (ClinicalTrials.gov identifier NCT03575351), a randomized, open-label, multicenter trial in adult patients with primary refractory LBCL or relapse within 12 months of achieving complete response to first-line therapy. Patients had not yet received treatment for relapsed or refractory lymphoma and were potential candidates for autologous HSCT.
A total of 184 patients were randomly assigned 1:1 to receive a single infusion of lisocabtagene maraleucel following fludarabine and cyclophosphamide lymphodepleting chemotherapy, or to receive second-line standard therapy consisting of three cycles of chemoimmunotherapy followed by high-dose therapy and autologous HSCT in patients who attained complete or partial response.
The primary efficacy measure was event-free survival as determined by an independent review committee. Event-free survival was significantly longer in the lisocabtagene maraleucel arm, with a hazard ratio of 0.34 (95% confidence interval [CI] = 0.22–0.52, P < .0001). The estimated 1-year event-free survival was 45% (95% CI = 29%–59%) in the lisocabtagene maraleucel arm and 24% (95% CI = 14%–35%) in the standard therapy arm. The estimated median event-free survival was 10.1 months (95% CI = 6.1 months–not evaluable) and 2.3 months (95% CI = 2.2–4.3 months), respectively.
Of patients randomly assigned to receive standard therapy, 47% received autologous HSCT as planned, with lack of response to chemotherapy being the most common reason for not receiving HSCT. The independent review committee–assessed progression-free survival was also significantly longer in the lisocabtagene maraleucel arm, with a hazard ratio of 0.41 (95% CI = 0.25–0.66, P < .0001).
Efficacy was also evaluated in TRANSCEND-PILOT-017006, (ClinicalTrials.gov identifier NCT03483103), a single-arm, open-label, multicenter trial in transplant-ineligible patients with relapsed or refractory LBCL after one line of chemoimmunotherapy. The study enrolled patients who were ineligible for high-dose therapy and HSCT due to organ function or age, but who had adequate organ function for CAR T-cell therapy. Efficacy was based on complete response rate and duration of response as determined by an independent review committee.
Of 74 patients who underwent leukapheresis (median age = 73 years), 61 (82%) received lisocabtagene maraleucel, of whom 54% (95% CI = 41%–67%) achieved complete response. The median duration of response was not reached (95% CI = 11.2 months–not reached) in patients who achieved complete response and 2.1 months (95% CI = 1.4–2.3 months) in patients with a best response of partial response. Among all leukapheresed patients, the complete response rate was 46% (95% CI = 34%–58%).
The FDA approved lisocabtagene maraleucel with a Risk Evaluation and Mitigation Strategy because of the risk of fatal or life-threatening cytokine-release syndrome and neurologic toxicities. In studies of lisocabtagene maraleucel as second-line therapy for LBCL, cytokine-release syndrome occurred in 45% of patients (grade 3 or higher = 1.3%), and neurologic toxicities occurred in 27% (grade 3 = 7%). Serious adverse reactions occurred in 33% to 38% of patients.
The recommended lisocabtagene maraleucel dose for second-line therapy is 90 to 110 × 106 CAR-positive T cells with a 1:1 ratio of CD4 and CD8 components.
This application was granted Priority Review, regenerative medicine advanced therapy designation, and Breakthrough Therapy designation. The application also received Orphan Drug designation.