FDA Postpones Review of BLA for Liso-Cel in R/R Large B-Cell Lymphoma

The FDA will not complete its review of the Biologics License Application (BLA) for lisocabtagene maraleucel (liso-cel), a chimeric antigen receptor (CAR) T-cell therapy for the treatment of patients with relapsed/refractory large B-cell lymphoma after 2 prior lines of therapy by the Prescription Drug User Fee Act action date of November 16, 2020, according to a press release from Bristol Myers Squibb.¹

Due to travel restrictions caused by the coronavirus disease 2019 (COVID-19) pandemic, the FDA was not able to conduct an inspection of a third-party manufacturing facility in Texas during the current review cycle. The FDA is deferring action until the inspection is completed, although the agency has not announced a new anticipated action date.

“Bristol Myers Squibb continues to work closely with the FDA to support the ongoing review of the BLA for liso-cel,” said Samit Hirawat, MD, executive vice president, chief medical officer, global drug development, Bristol Myers Squibb, in a statement. “We are committed to bringing liso-cel to patients with relapsed or refractory large B-cell lymphoma who still have significant unmet need.”

The BLA is supported the findings from the phase 1 TRANSCEND NHL 001 clinical trial, which evaluated the use of liso-cel as treatment of patients with relapsed/refractory large B-cell lymphoma, which included diffuse large B-cell lymphoma, high-grade lymphoma, primary mediastinal B-cell lymphoma, and grade 3b follicular lymphoma. This was the largest study of a CD19-directed CAR T-cell therapy to date in support of a BLA.

The multicenter, open-label randomized study included several co-primary end points. These included treatment-related adverse events, dose-limiting toxicities of liso-cel, and the overall response rate (ORR). Secondary end points included complete response (CR), duration of response, progression-free survival (PFS), overall survival (OS), and health-related quality of life.²

Among the 256 evaluable patients in this study, the ORR was 73% (95% CI, 67%-78%), and of the 187 patients who responded to liso-cel, 136 (53%) achieved a CR (95% CI, 47%-59%).

The responses were similar across all patient subgroups. The median duration of response was not reached (NR) in the overall population of patients (95% CI, 8.6 months-NR), at a median follow-up of 12 months (95% CI, 11.2-16.7).

The median PFS was 6.8 months (95% CI, 3.3-14.1), while the median OS was 21.1 months (95% CI, 13.3-NR). The median PFS and OS were NR among those who achieved a CR, with 12 months rates of 65.1% and 85.5%, respectively.

Overall, 79% of patients had experienced grade ≥3 treatment-emergent adverse events (TEAEs). The most common of these included neutropenia (60%), anemia (38%), and thrombocytopenia (27%). Thirty-seven percent of patients had prolonged grade ≥3 cytopenia.

Cytokine release syndrome (CRS) of any grade occurred in 42% of patients at a median onset of 5 days, and 2% had grade ≥3 CRS. Additionally, 30% of patients had neurologic events, 10% of which were grade 3 or higher, at a median onset of 9 days. CRS and neurologic events were ongoing in 8 patients at their time of death of another cause.

Grade 5 TEAEs related to liso-cel were observed in 4 patients, and these included diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome, and cardiomyopathy. Additionally, 3 grade 5 TEAEs were not related to the CAR T-cell therapy, including fludarabine leukoencephalopathy, septic shock, and progressive multifocal leukoencephalopathy.

_References

_{1. Bristol Myers Squibb Provides Regulatory Update on Lisocabtagene Maraleucel (liso-cel). News Release. Bristol Myers Squibb. November 16, 2020. Accessed November 16, 2020. https://bwnews.pr/3pKQMZI}

_{2. Bristol-Myers Squibb announces liso-cel met primary and secondary endpoints in TRANSCEND NHL 001 study. News Release. Bristol Myers Squibb. December 7, 2019. Accessed November 16, 2020. https://bit.ly/38ptnUx​}