On June 24, 2022, the FDA approved the CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (Breyanzi; Juno Therapeutics) for the treatment of adults with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal LBCL, and grade 3B follicular lymphoma.
The FDA granted lisocabtagene maraleucel regenerative medicine advanced therapy and breakthrough therapy designations for this indication. This approval includes a Risk Evaluation and Mitigation Strategy program, because of the risk for life-threatening or fatal cytokine release syndrome (CRS) and neurologic adverse events. This CAR T-cell therapy is not approved for primary central nervous system lymphoma.
Lisocabtagene maraleucel was previously approved for various subtypes of relapsed or refractory LBCL after ≥2 lines of systemic therapy.
“For more than 20 years, salvage chemotherapy followed by high-dose chemotherapy and stem cell transplant have been the mainstay of care for patients with second-line relapsed or refractory LBCL, but only a small portion of patients experience long-term benefit with this approach,” said Manali Kamdar, MD, Lead Investigator and Clinical Director of Lymphoma Services, Division of Hematology, Hematologic Malignancies and Stem Cell Transplantation, University of Colorado Cancer Center. “These results may pave the way for a practice-changing treatment approach where patients whose disease relapses or is refractory to frontline therapy can be treated with a personalized CAR T-cell therapy to increase the potential for improved outcomes.”
This indication was based on results of the TRANSFORM study, a global, randomized (1:1), multicenter, open-label clinical trial in 184 adults with primary refractory LBCL or with relapsed LBCL within 12 months of having a complete response. Patients were randomized to a single infusion of lisocabtagene maraleucel after lymphodepleting chemotherapy or to second-line therapy with 3 cycles of salvage chemotherapy, followed by high-dose therapy and autologous hematopoietic stem-cell transplant in patients who had a partial or complete response.
The primary efficacy measure was event-free survival (EFS). The results showed a significant improvement in EFS with the CAR T-cell therapy versus the standard of care (hazard ratio [HR], 0.34; 95% confidence interval [CI], 0.22-0.52; P <.0001); the 1-year EFS rates were 45% and 24%, respectively. The median EFS was 10.1 months with lisocabtagene maraleucel (95% CI, 6.1-nonevaluable) versus 2.3 months with the standard of care (95% CI, 2.2-4.3).
The median progression-free survival was 14.8 months with lisocabtagene maraleucel and 5.7 months with the standard of care (HR, 0.406; P = .0001).
The majority (86%) of the patients who received lisocabtagene maraleucel achieved a partial or complete response, including 66% complete responses, compared with 48% of patients in the standard-of-care arm achieving partial or complete responses, including 39% complete responses.
Lisocabtagene maraleucel had a manageable safety profile, with 49 patients having any-grade CRS, 1 patient had grade 3 CRS, and no grade 4 or 5 CRS reported. In all, 12% of the patients who received the CAR T-cell therapy had any-grade neurologic events, including 4% grade 3 events.