The FDA will not complete its review of the Biologics License Application for lisocabtagene maraleucel 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.
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.
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