Bristol-Myers Seeks FDA Approval of CAR T-cell Therapy Liso-Cel for Aggressive Large B-cell Lymphomas

Bristol-Myers Seeks FDA Approval of CAR T-cell Therapy Liso-Cel for Aggressive Large B-cell Lymphomas

Bristol-Myers Squibb has asked the U.S. Food and Drug Administration (FDA) to approve its investigational CAR T-cell therapy lisocabtagene maraleucel (liso-cel) for people with large B-cell lymphoma who received at least two prior therapies, the company said in a press release.

The biologics license application was based on the latest data from the multicenter Phase 1 TRANSCEND NHL 001 trial (NCT02631044), in which the treatment completely eliminated traces of cancer in more than half (53%) of the diffuse large B-cell lymphoma (DLBCL) patients included in the trial, and partially reduced tumor volume in another 20%.

Updated results from the trial were presented last month at the American Society of Hematology (ASH) 2019 Annual Meeting in San Diego, in a study titled, “Pivotal Safety and Efficacy Results from Transcend NHL 001, a Multicenter Phase 1 Study of Lisocabtagene Maraleucel (liso-cel) in Relapsed/Refractory (R/R) Large B Cell Lymphomas.”

Liso-cel (previously known as JCAR017) is an immunotherapy candidate originally developed by Juno Therapeutics and Celgene, both of which are now part of Bristol-Myers, to treat patients with aggressive forms of B-cell non-Hodgkin’s lymphoma who have not responded well to other treatments.

The investigational medication is a chimeric antigen receptor (CAR) T-cell therapy, a type of treatment that involves collecting a patient’s own immune T-cells and modifying them in the lab to target a specific cancer protein. The genetically engineered cells are then expanded to millions in bioreactors and inserted back into the patient, where they help fight the tumor.

TRANSCEND-NHL-001 is testing the safety and efficacy of liso-cel in relapsed or refractory patients with large B-cell lymphoma, including DLBCL, primary mediastinal B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma.

The latest analysis included 269 B-cell lymphoma patients who received ascending doses of liso-cel: 50 million cells (51 patients), 100 million cells (176 patients), or 150 million cells (41 patients), given as a single into-the-vein (intravenous) injection.

Patients had a median age of 63 years, were mostly male (65%), and had heavily treated and aggressive disease. Some 26% had received four or more prior lines of therapy, 34% a prior stem cell transplant, 67% were resistant to chemotherapy, and 44% had never achieved a complete response.

While the 100 million-cell dose was selected as the optimal dose to continue studying the treatment, researchers said that outcomes were similar between dose groups and presented pooled data from the three groups.

At the time of the analysis, 256 had been assessed for efficacy. Overall, 73% of them had a response to treatment, including 53% who had no traces of cancer cells after treatment. Responses lasted a median of 13.3 months.

The median overall survival was 21.1 months, and the median time to disease progression or death (a measure called progression-free survival, or PFS) was 6.8 months, which “was substantially longer than PFS from the immediate prior therapy,” the researchers wrote.

Survival outcomes were even better for patients who achieved a complete response to liso-cel, with 65.1% being progression-free and 85.5% being alive at one year.

“These pivotal longer-term results from TRANSCEND NHL 001 continue to give us confidence in the clinical profile of liso-cel. Importantly, these results were demonstrated in a study with more than 250 patients in a broad population reflective of clinical practice, including those with poor prognoses and a range of histologies,” Stanley Frankel, MD, senior vice president of cellular therapy development for Bristol-Myers Squibb, said in a press release reporting the Phase 1 findings.

Serious (grade 3-5) treatment-related adverse events were reported in 79% of patients and included neutropenia (low levels of immune cells called neutrophils), anemia, and thrombocytopenia (low platelet counts).

Cytokine release syndrome (CRS), a form of systemic inflammatory response that can result from treatment with CAR T-cells, occurred in 113 patients (42%), but only six (2%) had severe or life-threatening CRS. Thirty percent had neurological side effects, 10% of which were severe.

“Longer-term follow-up from the TRANSCEND study shows that liso-cel resulted in a rapid, high rate of durable complete responses with low incidence of severe cytokine release syndrome and neurologic events in 2% and 10%, respectively, among patients with relapsed/refractory large B-cell lymphomas,” said Jeremy Abramson, MD, associate professor of medicine at Harvard Medical School and director of the Lymphoma Center at Massachusetts General Hospital.

In another ASH presentation, researchers reported data from questionnaires assessing quality of life in patients who received liso-cel in the TRANSCEND trial. The results showed that patients experienced improvements in overall and health-related quality of life, including less fatigue and fewer pain symptoms.

The FDA designated liso-cel a breakthrough therapy and regenerative medicine advanced therapy for aggressive relapsing or refractory B-cell NHL. In Europe, the European Medicines Agency granted liso-cel access to its priority medicines scheme. Such designations help speed the time it takes for a potential treatment to move through the development and approval process.

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