FDA has approved Breyanzi ( Lisocabtagene maraleucel ), a new CAR T cell therapy for adults with relapsed or refractory large B-cell lymphoma


The U.S. Food and Drug Administration ( FDA ) has approved 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 ( 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 ( including DLBCL arising from indolent lymphoma ), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.
Breyanzi is not indicated for the treatment of patients with primary central nervous system lymphoma.

Breyanzi is a CD19-directed CAR T cell therapy with a defined composition and 4-1BB costimulatory domain.
Breyanzi is administered as a defined composition to reduce variability of the CD8 and CD4 component dose. The 4-1BB signaling enhances the expansion and persistence of Breyanzi.
Breyanzi offers a potentially definitive treatment. A single dose of Breyanzi contains 50 to 110 x 10(6) CAR-positive viable T cells ( consisting of 1:1 CAR-positive viable T cells of the CD8 and CD4 components ).

The FDA approval of Breyanzi is based on data from the TRANSCEND NHL 001 trial in which 268 patients with R/R LBCL received Breyanzi, the largest pivotal trial in third-line plus R/R LBCL that included patients with a broad range of histologies and high-risk disease.
In the trial, Breyanzi was administered in the inpatient and outpatient settings.

In the study, 192 patients were treated with Breyanzi at the dose of 50 to 110 x 10(6) CAR-positive viable T cells and evaluated for efficacy. Of these patients, 73% achieved a response ( 95% CI: 67-80% ), including 54% who had minimal or no detectable lymphoma remaining following treatment ( CR; 95% CI: 47-61% ) and 19% who achieved a partial response ( PR; 95% CI: 14-26% ).
Median duration of response was 16.7 months in all responders ( 95% CI: 5.3 – NR ), and for patients who achieved a CR, median duration of response was not reached ( 95% CI: 16.7 – NR ); for patients with a best response of PR, median duration of response was 1.4 months ( 95% CI: 1.1 – 2.2 ). Of 104 patients treated with Breyanzi who achieved a best overall response of CR, 65% had remission lasting at least six months and 62% had remission lasting at least nine months.

In the study, 268 patients treated with Breyanzi were evaluated for safety. Any grade cytokine release syndrome ( CRS ) occurred in 46% ( 122/268 ) of patients using the Lee grading system. Grade 3 or more CRS occurred in 4% ( 11/268 ) of patients. One patient had fatal CRS and two 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 five days ( range: 1-30 days ) and median time to onset was five days ( range: 1-15 days ).

Any grade neurologic toxicities occurred in 35% ( 95/268 ) of patients receiving Breyanzi. Grade ≥3 neurologic toxicities occurred in 12% ( 31/268 ) of patients. Three patients had fatal neurologic toxicity and seven had ongoing neurologic toxicity at time of death. The most common neurologic toxicities included encephalopathy ( 24% ), tremor ( 14% ), aphasia ( 9% ), delirium ( 7% ), headache ( 7% ), ataxia ( 6% ), and dizziness ( 6% ). Neurologic toxicities resolved in 81 of 95 patients ( 85% ), with a median duration of 12 days ( range: 1-87 days ). The median time to onset of the first event was eight days ( range: 1-46 days ). Median duration of neurologic toxicity was 15 days ( range: 1 to 785 days ) in all patients, including those with ongoing neurologic events at the time of death or at data cutoff.

Serious adverse reactions occurred in 46% of patients. The most common nonlaboratory, serious adverse reactions ( more than 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 nonlaboratory adverse reactions of any grade ( 20% or more ) were fatigue, CRS, musculoskeletal pain, nausea, headache, encephalopathy, infections ( pathogen unspecified ), decreased appetite, diarrhea, hypotension, tachycardia, dizziness, cough, constipation, abdominal pain, vomiting, and edema.

Diffuse large B-cell lymphoma is a rapidly growing, aggressive disease and the most common form of non-Hodgkin lymphoma ( NHL ), accounting for one out of every three cases diagnosed.
Seventy-three percent of patients will not respond to or will relapse following second-line treatment or later.
For patients who relapse or do not respond to initial therapies, conventional treatment options that provide sustained responses are limited and median life expectancy is about six months.
The goal of treatment in DLBCL is curative intent with definitive therapy.
Additional options are needed in R/R DLBCL to deliver sustained responses to these patients. ( Xagena )

Source: BMS, 2021

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