Brief Introduction of CAR-T Cell Therapy Breyanzi (Lisocabtagene Maraleucel)
Brief Introduction of CAR-T Cell Therapy Breyanzi (Lisocabtagene Maraleucel)
Breyanzi Brief Introduction
Breyanzi (Lisocabtagene Maraleucel) is a CAR-T therapy developed by the global biopharmaceutical company Bristol Myers Squibb (BMS). Breyanzi is a CD-19 directed chimeric antigen receptor (CAR) T-cell therapy, administered as a defined composition to reduce variability in the doses of CD8 and CD4 components. Breyanzi has a 4-1BB co-stimulatory domain, which can enhance the proliferation and persistence of CAR T cells.
Marketing Approval Overview of Breyanzi
Initial FDA Approval
On February 5, 2021, BMS announced that the FDA had approved the CAR-T cell therapy Breyanzi (lisocabtagene maraleucel; liso-cel) for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B. However, Breyanzi is not indicated for the treatment of patients with primary central nervous system lymphoma.
This approval was based on data from the TRANSCEND NHL 001 (017001) study. A total of 268 patients with R/R LBCL received Breyanzi treatment, making it the largest key trial in the third-line or later treatment of R/R LBCL.
Among the 192 patients evaluable for efficacy, 73% (95% CI: 67%-80%) achieved a response, with 54% (95% CI: 47%-61%) achieving a complete response (CR) and 19% (95% CI: 14%-26%) achieving a partial response (PR). Among all responding patients, the median duration of response was 16.7 months (95% CI: 5.3-NR); for patients achieving CR, the median duration of response was not reached (95% CI: 16.7-NR); for patients with a best response of PR, the median duration of response was 1.4 months (95% CI: 1.1-2.2). Among the 104 patients who received Breyanzi and achieved a best overall response of CR, 65% had a response lasting at least 6 months, and 62% had a response lasting at least 9 months.
Safety was evaluated in 268 patients who received Breyanzi treatment in the study. Using the Lee criteria, 46% (122/268) of patients experienced cytokine release syndrome (CRS), with 4% (11/268) experiencing Grade 3 or higher CRS. One patient died with ongoing CRS, and two patients had ongoing CRS at the time of death. The most common manifestations of CRS included fever (93%), hypotension (49%), tachycardia (39%), chills (28%), and hypoxia (21%). The median duration of CRS was 5 days, with a median time to onset of 5 days.
Among patients who received Breyanzi, 35% (95/268) experienced neurologic toxicity (NT), with 12% (31/268) experiencing Grade 3 or higher NT. One patient died with ongoing NT, and seven patients had ongoing NT at the time of death. The most common NTs included encephalopathy (24%), tremor (14%), aphasia (9%), delirium (7%), headache (7%), ataxia (6%), and dizziness (6%). Eighty-one of the 95 patients (85%) with NT had resolution, with a median duration of 12 days and a median time to onset of 8 days. The median duration of NT for all patients, including those who died or had ongoing NT at the data cutoff, was 15 days.
Forty-six percent of patients experienced serious adverse reactions. The most common (>2%) were CRS, encephalopathy, sepsis, febrile neutropenia, aphasia, pneumonia, fever, hypotension, dizziness, and delirium. Fatal adverse reactions occurred in 4% of patients. The most common adverse reactions of any grade (≥20%) included fatigue, CRS, musculoskeletal pain, nausea, headache, encephalopathy, infection, decreased appetite, diarrhea, hypotension, tachycardia, dizziness, cough, constipation, abdominal pain, vomiting, and edema.
Second FDA Approval
On June 24, 2022, BMS announced that its marketed CAR-T product Breyanzi had received an additional indication from the FDA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) after one prior line of therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
– Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or
– Refractory disease 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.
This second-line indication approval was based on the results of the phase III TRANSFORM clinical trial. On June 10, 2021, BMS announced that its CD19-targeted CAR-T cell therapy lisocabtagene maraleucel met the primary and key secondary endpoints in the phase III TRANSFORM trial, significantly improving event-free survival, complete response rates, and progression-free survival compared to standard therapy in patients with relapsed/refractory large B-cell lymphoma (LBCL). Data reported at the 2021 ASH meeting with a median follow-up of 6.2 months showed that liso-cel significantly prolonged the primary endpoint of event-free survival (EFS) compared to standard therapy, with a median EFS of 10.1 months (95% CI: 6.1-NR) for liso-cel and 2.3 months (95% CI: 2.2-4.3) for standard therapy, HR=0.349, p<0.0001.
Third FDA Approval
On March 14, 2024, Bristol Myers Squibb announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval to Breyanzi® (lisocabtagene maraleucel; liso-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least two prior therapies, including a Bruton’s tyrosine kinase (BTK) inhibitor and a BCL-2 inhibitor.
This approval was based on the results of the phase 1/2 TRANSCEND CLL 004 trial, which were presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. The study enrolled adult patients with relapsed or refractory CLL or SLL after progression on a BTK inhibitor and a BCL-2 inhibitor. In this trial, 117 patients received this treatment, and 96 were evaluable. The trial showed an objective response rate of 45%. The median duration of response for responding patients was 35.3 months. The complete response rate in patients receiving this treatment was 20%. The median duration of complete response has not yet been reached for patients achieving a complete response. The researchers also found a high rate of minimal residual disease (MRD) negativity in patients achieving a complete response, with 92.3% and 100% MRD negativity rates in bone marrow and blood, respectively.
European Union Approval
On May 3, 2023, Bristol Myers Squibb announced that the European Commission (EC) has approved Breyanzi (lisocabtagene maraleucel; liso-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, for the treatment of adult patients with:
– Diffuse large B-cell lymphoma (DLBCL)
– High-grade B-cell lymphoma (HGBCL)
– Primary mediastinal large B-cell lymphoma (PMBCL)
– Follicular lymphoma grade 3B (FL3B)