FDA Approves Liso-Cel CAR T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma

The FDA has granted approval to lisocabtagene maraleucel (liso-cel; Breyanzi), a CD19-targeting chimeric antigen receptor (CAR) T-cell therapy, for the treatment of adult patients with relapsed or refractory large B-cell lymphoma who have received at least 2 prior lines of systemic therapy.¹

Liso-cel is now the third gene therapy approved by the FDA for specific types of non-Hodgkin lymphoma. However, the CAR T-cell therapy is not indicated for the treatment of patients with primary central nervous system lymphoma.

"Today's approval represents another milestone in the rapidly progressing field of gene therapy by providing an additional treatment option for adults with certain types of cancer affecting the blood, bone marrow, and lymph nodes," said Peter Marks, MD, PhD, director of the FDA's Center for Biologics Evaluation and Research, in a statement. "Gene and cell therapies have evolved from promising concepts to practical cancer treatment regimens."

The approval of liso-cel is based on primary findings from the phase 1 TRANSCEND NHL 001 study, which met its primary and secondary end points. The co-primary end points were treatment-related adverse events (AEs), the dose-limiting toxicities (DLTs) of liso-cel, and objective response rate (ORR). Secondary end points included complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and health-related quality of life. Overall, 256 patients of 344 total patients who underwent leukapheresis were evaluable for efficacy in the study.²

The ORR was 73% (95% CI, 66.8%-78.0%), which included 186 total responses. More than half (53%) of the patients had achieved a CR (95% CI, 46.8%-59.4%). The median DOR was not reached (NR) yet in the overall population (95% CI, 8.6-NR), but the DOR at 6 months was 60.4% (95% CI, 52.6-67.3) and at 12 months was 54.7% (95% CI, 46.7-62.0).

The median PFS was 6.8 months (95% CI, 3.3-14.1), with the 6-month and 12-month PFS rates being 51.4% (95% CI, 44.6-57.7) and 44.1% (95% CI, 37.3-50.7). The median OS was 21.1 months (95% CI, 13.3-NR), and the 6-month OS rate was 74.7% (95% CI, 68.9-79.6), with the 12-month rate at 57.9% (95% CI, 51.3-63.8).

According to the safety analysis, 79% of patients experienced grade ≥3 treatment-emergent AEs (TEAEs), including neutropenia in 60% of patients, anemia in 37%, and thrombocytopenia in 27%. Additionally, 37% of patients experience prolonged grade ≥3 cytopenia.

Overall, 7 patients died with TEAES, and causes included diffuse alveolar damage (DLT), pulmonary hemorrhage, multiple organ dysfunction syndrome, and cardiomyopathy, deemed related to both liso-cel and lymphodepleting chemotherapy by the investigators; fludarabine-associated leukoencephalopathy and septic shock, related to lymphodepleting chemotherapy; and progressive multifocal leukoencephalopathy, unrelated to either treatment.

Cytokine release syndrome (CRS) was observed in 42% of patients in any grade, with the median time to onset of CRS being 5 days (range, 1-14). Grade ≥3 CRS occurred in only 2% of patients. The median time to resolution of CRS was 5 days (range, 1-17).

Neurologic events occurred in 30% of patients, with 10% being grade 3 or higher in severity, and the median time to onset was 9 days (range, 1-66). The median time to resolution was 11 days (range, 1-86).

A higher incidence of CRS and neurological events was observed among patients who had a high tumor burden or increased inflammatory markers, as well as those who received a bridging therapy.

The multicenter, open-label, nonrandomized study remains ongoing. The study enrolled patients with heavily pretreated and aggressive disease, with a median of 3 prior therapies. Thirty-five percent of the patients enrolled had undergone autologous or allogeneic hematopoietic stem cell transplant as a prior therapy, and 67% of patients had chemotherapy-refractory disease.

The study includes patients with relapsed/refractory B-cell non-Hodgkin lymphoma who are aged 18 years or older. They must have a PET-positive disease by Lugano classification, an ECOG performance status of 0 or 1, an archived tumor biopsy tissue available from last relapse and corresponding pathology report or at least 1 tumor-involved site accessible at screening, and adequate bone marrow and vascular function. They must have received prior CD19-targeted therapy but must have CD19-positive lymphoma confirmed by a biopsy since the time of prior therapy.

Patients are ineligible if they had prior treatment with corticosteroids, low-dose chemotherapy, cytotoxic chemotherapeutic agents, lymphotoxic chemotherapeutic agent, immunosuppressive therapies, donor lymphocyte infusions, radiation, and allogeneic hematopoietic stem cell transplantation within a certain number of day or weeks before starting treatment on the study. Patients with certain comorbidities were also excluded.

The initial action date set for this agent, August 17, 2020, was extended by 3 months as a result of additional information on the drug that was submitted after the Biologics License Application (BLA). The inclusion of this information following the BLA submission required a significant amendment to the application, which took the FDA more time to review before making decision on this approval.³

Due to the risk of CRS and neurological toxicities, liso-cel was approved with a risk evaluation and minitation strategy (REMS) program, and the FDA has required that facilities administering liso-cel be certified.¹

A post-marketing observational study has also been required to further assess long-term safety of the CAR T-cell therapy.

_References:

_{1. FDA Approves New Treatment For Adults With Relapsed Or Refractory Large-B-Cell Lymphoma. News release. FDA. February 5, 2021. Accessed February 5, 2021. https://yhoo.it/3cXR4bN} 

_{2. Abramson, JS, Palomba, ML, Gordon, LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. The Lancet. 2020;396(10254);839-852. doi:10.1016/s0140-6736(20)31366-0}

_{3. B ristol Myers Squibb provides update on biologics license application (BLA) for lisocabtagene maraleucel (liso-cel). News Release. Bristol Myers Squibb. May 6, 2020. Accessed DATE, 2020. https://bit.ly/2YFWAs8}