Bristol Myers Squibb Submits Marketing Application in Japan for CAR-T Therapy Lisocabtagene Maraleucel for Relapsed/Refractory Large B-Cell Lymphoma

Recently, Bristol-Myers Squibb K.K., the Japanese subsidiary of Bristol-Myers Squibb (BMS), announced that it has submitted a marketing application for lisocabtagene maraleucel (hereinafter referred to as liso-cel, JCAR017) in Japan. The submission falls under the category of regenerative medicine, with the indication being the treatment of adult patients with relapsed/refractory large B-cell lymphoma (LBCL) who have failed at least two prior systemic therapies. This marks the second country where liso-cel has been submitted for marketing approval; last year, liso-cel was submitted to the U.S. FDA and is currently under review.

It is understood that liso-cel was developed by Juno Therapeutics (which Celgene acquired in January 2018 for $9 billion). This is a CAR-T cell therapy targeting the CD19 antigen and utilizing 4-1BB as the co-stimulatory domain, featuring a precise 1:1 ratio of CD4+ and CD8+ CAR-T cells to better control the toxic side effects associated with cell therapy. Previously, liso-cel had been granted Breakthrough Therapy Designation and Regenerative Medicine Advanced Therapy (RMAT) designation by the U.S. FDA. In early January last year, Bristol-Myers Squibb announced its acquisition of Celgene for $74 billion. After experiencing a series of setbacks, this massive acquisition was successfully completed on November 21, 2019, thereby bringing liso-cel under the ownership of Bristol-Myers Squibb.

It is understood that this application is based on safety and efficacy data from a clinical trial coded TRANSCEND NHL 001, conducted in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL), as well as from a global Phase II study involving Japanese patients with relapsed or refractory aggressive B-NHL.

The TRANSCEND NHL 001 trial enrolled a total of 269 patients with relapsed/refractory large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL). Data showed that among efficacy-evaluable patients (n=256), the overall response rate (ORR) to liso-cel treatment was 73% (187/256; 95% CI: 67–78), and the complete response rate (CR) was 53% (136/256; 95% CI: 47–59). Responses were similar across all patient subgroups. With a median follow-up of 12 months (95% CI: 11.2–16.7), the median duration of response (DOR) was not reached (95% CI: 8.6–NR). The median progression-free survival (PFS) was 6.8 months (95% CI: 3.3–14.1), and the median overall survival (OS) was 21.1 months (95% CI: 13.3–NR). Among patients who achieved complete response, the median PFS and OS were not reached; at 12 months, 65.1% of patients remained progression-free and 85.5% were alive.

In terms of safety, 79% (213/269) of all patients experienced Grade 3 or higher treatment-emergent adverse events (TEAEs), including neutropenia, anemia, and thrombocytopenia. Cytokine release syndrome (CRS) occurred in 42% (113/269) of patients, with a median onset of 5 days, while 2% (6/269) of patients experienced Grade 3 or higher CRS. Neurologic events (NEs) occurred in 30% (80/269) of patients, with 10% (27/269) experiencing Grade 3 or higher NEs.

The submission of the marketing application for liso-cel is expected to make it the third CAR-T cell therapy approved for market launch, following Novartis’s Kymriah and Gilead Sciences’ Yescarta (axicabtagene ciloleucel), a CD19-targeted CAR-T cell therapy.

In fact, liso-cel is not the first CAR-T therapy submitted by Bristol-Myers Squibb. In April this year, Bristol-Myers Squibb and bluebird bio (Bluebird) announced that they had submitted a Biologics License Application (BLA) to the U.S. FDA for their CAR-T therapy idecabtagene vicleucel (ide-cel, also known as bb2121), for the treatment of patients with relapsed/refractory multiple myeloma (R/R MM). This is the first globally submitted marketing application for a BCMA-targeted CAR-T therapy.

The bb2121 therapy involves chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen (BCMA). In the treatment regimen, patients with multiple myeloma (MM) first undergo preconditioning with two chemotherapy drugs, cyclophosphamide and fludarabine, to deplete their existing T cells. Subsequently, BCMA-targeted CAR-T cells are infused to identify and eliminate MM cells expressing BCMA. This therapy has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) and Priority Medicines (PRIME) status by the European Medicines Agency (EMA).

Original Title: [Cell Therapy] Bristol-Myers Squibb Submits Marketing Application for a CAR-T Therapy in Japan, Potentially Becoming the Third CAR-T Therapy in Japan