Lisocabtagene maraleucel for the treatment of adults with relapsed or refractory (R/R) large B-cell lymphoma: Regulatory Update

Highlights
- Lisocabtagene Maraleucel (liso-cel) is an investigational drug for the treatment of adults with relapsed or refractory (R/R) large B-cell lymphoma 
- Developed by Bristol Myers Squibb (BMS) (Previously Juno Therapeutics)
- Biologics License Application (BLA) is under review by FDA, and the review will not be completed by the PDUDA data 
- MAA is under review by EMA
- In the clinical study, the use of liso-cel resulted in a high objective response rate (primary endpoint), with a low incidence of grade 3 or worse cytokine release syndrome

Lisocabtagene maraleucel is an investigational, autologous, CD19-directed CAR T-cell product with a 4-1BB co-stimulatory domain, which is administered as a sequential infusion of two components (CD8+ and CD4+ CAR+ T-cells) at equal target doses.

Regulatory Status

U.S. Food and Drug Administration (FDA)
November 2020: U.S. Food and Drug Administration (FDA) has informed the company that its review of the Biologics License Application (BLA) for lisocabtagene maraleucel (liso-cel) for the treatment of adults with relapsed or refractory (R/R) large B-cell lymphoma after at least two prior therapies will not be completed by the Prescription Drug User Fee Act (PDUFA) action date of November 16, 2020.

European Medicines Agency (EMA) 
July 2020: The European Medicines Agency (EMA) has validated its Marketing Authorization Application (MAA)

Clinical Result Update

Results of the TRANSCEND study show that lisocabtagene maraleucel, an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product causes low incidence of all grade and severe cytokine release syndrome and neurological events and can lead to rapid and durable remission among patients with high-risk aggressive relapsed or refractory large B-cell lymphomas. The clinically meaningful activity was noted across populations with unmet medical need, including uncommon histological subtypes and patients with characteristics of poor prognosis. 

Study Design Summary (TRANCEND- Published in Lancet)

Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR+ T cells (liso-cel), of whom 269 patients received at least one dose of liso-cel. 
Patients had received a median of three (range 1-8) previous lines of systemic treatment, with 260 (97%) patients having had at least two lines. 112 (42%) patients were aged 65 years or older, 181 (67%) had chemotherapy-refractory disease, and seven (3%) had secondary CNS involvement. 

Median follow-up for overall survival for all 344 patients who had leukapheresis was 18·8 months (95% CI 15·0-19·3). Overall safety and activity of liso-cel did not differ by dose level. The recommended target dose was 100 × 106 CAR+ T cells (50 × 106 CD8+ and 50 × 106 CD4+ CAR+ T cells). 

Efficacy: 
Of 256 patients included in the efficacy-evaluable set, an objective response (Primary Endpoint)  was achieved by 186 (73%, 95% CI 66·8-78·0) patients and a complete response by 136 (53%, 46·8-59·4). 

Safety
  • The most common grade 3 or worse adverse events were neutropenia in 161 (60%) patients, anaemia in 101 (37%), and thrombocytopenia in 72 (27%). 
  • Cytokine release syndrome and neurological events occurred in 113 (42%) and 80 (30%) patients, respectively; grade 3 or worse cytokine release syndrome and neurological events occurred in six (2%) and 27 (10%) patients, respectively. 
  • Nine (6%) patients had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 × 106 CAR+ T cells.
Reference
www.bms.com
Abramson JS, Palomba ML, Gordon LI, et al. https://doi.org/10.1016/S0140-6736(20)31366-0 



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