FDA Extends Target Action Date for Liso-cel in R/R Large B-cell Lymphoma

The action date for the CD19-directed chimeric antigen receptor (CAR) T cell therapy lisocabtagene maraleucel (liso-cel) as treatment of adult patients with relapsed or refractory large B-cell lymphoma after at least 2 therapies, was extended 3 months by the FDA. The updated Prescription Drug User Fee Act (PDUFA) action date is November 16, 2020, Bristol Myers Squibb (BMS) announced in a press release.¹

Extending the decision on liso-cel was a result of additional information on the drug, that was submitted after the Biologics License Application (BLA). The information will require a significant amendment to the application which will take the FDA more time to review. BMS plans to work closely with the FDA as they review the BLA for liso-cel.

Liso-cel was originally granted Priority Review by the FDA for this indication based on data from the phase I TRANSCEND NHL 001 trial, which evaluated 255 patients with relapsed/refractory large B-cell lymphoma for efficacy.

According to data presented at the Transplantation & Cellular Therapy (TCT) Meetings, liso-cel achieved a 73% objective response rate (95% CI, 67-78) with complete responses (CRs) observed in 53% (95% CI, 47-59) of patients and partial responses were seen in 20%. Also, 11% of patients had stable disease.²

Results previously published in Blood, showed similarity across the various subgroups of patients in the study, which included patients who were older (≥65 yrs, 41%; ≥75 yrs, 10%), heavily pretreated, had aggressive disease, had 4 or more prior lines of systemic therapy, underwent prior autologous stem cell transplant, had prior allogeneic stem cell transplant, were chemotherapy-refractory, and had never achieved a CR.³

With 10.8-month median follow-up, the median duration of response (DOR) observed with liso-cel was 13.3-month (95% CI, 8.2-not reached [NR]). Among patients who achieved a CR, the median DOR was NR (range, 13.3-NR).

In terms of survival, the median progression-free survival (PFS) was 6.8 months (95% CI, 3.3-11.8), and the median overall survival (OS) was 19.9 months (95% CI, 10.9-NR). The investigators noted that a longer PFS was observed after liso-cel induction versus the immediate prior therapy.

Results from the safety analysis showed that 3 or more treatment-emergent adverse events (TEAEs) occurred in 79% of patients, which were most commonly neutropenia (60%), anemia (37%), and thrombocytopenia (27%). Central nervous system or neurological events (NEs_ were seen in 47% of patients.

Of the CRS events, 42% occurred within 5 days of treatment, and only 2% were high-grade events. Thirty percent of patients who experienced NEs had a median onset of 9 days, and 10% of these cases were grade 3 or higher. There were 4 grade 5 TEAEs that were related to treatment, including diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome, and cardiomyopathy. Additionally, 37% of patients reported prolonged grade 3 or higher cytopenia. Overall, the safety profile of liso-cel was favorable and consistent across the different age groups, histologies, and patients with organ dysfunction.

The co-primary end points of the multicenter, open-label study were ORR, treatment-related adverse events, and dose-limiting toxicities. The secondary end points were CR rate, DOR, PFS, and OS. The study met all of it primary and secondary end points. The efficacy findings were considered to be clinically meaningful.

_References:

_{1. Bristol Myers Squibb provides update on biologics license application (BLA) for lisocabtagene maraleucel (liso-cel) [news release]. Princeton, New Jersey: Bristol Myers Squibb; May 6, 2020. https://bit.ly/2YFWAs8. Accessed May 6, 2020.}

_{2. Bachier CR, Palomba ML, Abramson JA, et al. Outpatient treatment with lisocabtagene maraleucel (liso-cel) in 3 ongoing clinical studies in relapsed/refractory (R/R) large B cell non-Hodgkin lymphoma (NHL), including second-line transplant noneligible (TNE) patients: TRANSCEND NHL 001, OUTREACH, and PILOT. Presented at: 2020 Transplantation & Cellular Therapy Meetings; February 19-23, 2020. Orlando, FL. Abstract 29. https://bit.ly/37I7DC9.}

_{3. bramson JS, Palomba ML, Gordon LI, et al. 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. Blood. 2019;134 (1); 241. doi: 10.1182/blood-2019-127508}