January 4, 2021 - The biologics license application for the CAR T-cell product lisocabtagene maraleucel in adult patients with relapsed/refractory large B-cell lymphoma following at least 2 previous therapies continues to be under regulatory review by the FDA, and a decision on the application has not yet been reached.
The biologics license application (BLA) for the CAR T-cell product lisocabtagene maraleucel (liso-cel) in adult patients with relapsed/refractory large B-cell lymphoma following at least 2 previous therapies continues to be under regulatory review by the FDA, and a decision on the application has not yet been reached.1
A new action date for the application has yet to be provided by the regulatory agency. Bristol Myers Squibb announced that it will continue to work with the FDA to support the ongoing review of the BLA.
Moreover, because the approval of the product did not occur by December 31, 2020, 1 of the 3 milestones required for the payment of the Bristol Myers Squibb Contingent Value Right (CVR) had not been met.
As such, on January 1, 2021, the CVR Agreement, pursuant to which the CVRs were delivered, underwent automatic termination in accordance with its terms. Moreover, the CVRs are no longer eligible for payment under the CVR Agreement, and thus, the CVRs will no longer trade on the NYSE.
Previously, in November 2020, the pharmaceutical company announced that the review of the BLA for liso-cel would be delayed because the FDA had not been able to conduct an inspection of a third-party manufacturing facility based in Texas during the review cycle in light of travel restrictions that were put into place in response to the coronavirus disease 2019 pandemic.2
The initial decision date that was set for the application was August 17, 2020. However, in May 2020, the FDA extended the review period for liso-cel by 3 months to allow for the analysis of additional data supplied by Bristol Myers Squibb.3
The application had been based on data yielded from the phase 1 TRANSCEND NHL 001 trial (NCT02631044), which showed that liso-cel induced an objective response rate of 73% in this population; this included a complete response (CR) rate of 53%. Responses to the product were rapid, with a time to first CR or partial response in these patients being a median of 1 month.4
Additionally, at a median of 12 months, the median duration of response with liso-cel had not yet been reached. At 6 months, more than half of patients, or about 60%, continued to experience a response to the CAR T-cell product; at 12 months, 54.7% continued to respond to treatment.
Moreover, data presented during the 2019 ASH Annual Meeting indicated that the median progression-free survival achieved with liso-cel was 6.8 months (95% CI, 3.3-14.1) and 44% of patients continued to be free of disease progression at the time of the presentation. The median overall survival reported with the CAR T-cell product was 21.1 months (95% CI, 13.3–not reached). At 1 year, 58% of patients who received the agent were still alive; the majority of these patients, or 86%, were those who had experienced a CR.
A total of 344 participants with LBCL were enrolled to TRANSCEND NHL 001; these patients had previously received 2 or more lines of therapy and had undergone leukapheresis. Additionally, 269 of participants were given liso-cel at 1 of the following 3 doses: 50 × 106 (n = 51), 100 × 106 (n = 177), and 150 × 106 (n = 41).
Patients with high-risk characteristics like secondary central nervous system involvement or those with moderate medical comorbidities were eligible to participate. No lower limit of absolute lymphocyte count was defined for eligibility. Patients were also allowed to have bridging therapy after leukapheresis if they required urgent control of their disease; this was decided by the study investigator. Patients underwent 3 days of lymphodepleting therapy with fludarabine and cyclophosphamide before they received the CAR T-cell infusion.
A total of 25 patients had been given nonconforming product that did not meet all specifications for the CAR T-cell therapy. Because of this, these patients were excluded from the primary analysis dataset. In 2 cases, liso-cel was unable to be manufactured.
Moreover, 13 patients who received the CAR T-cell infusion were excluded from the efficacy analysis. Four patients did not have positron emission tomography (PET)–positive LBCL before receiving liso-cel, 6 patients did not undergo a PET scan after their bridging therapy, and 3 were excluded for other reasons. A total of 256 patients comprised the efficacy population.
Additional results indicated that responses achieved with liso-cel were similar across all subgroups examined, which included those with different disease histologies and high-risk characteristics. Participants who had the highest tumor burden were found to have lower CR rates with liso-cel, as were those who received bridging therapy. Regardless, these patients still responded to treatment with the product.
Moreover, the 25 participants who had received a nonconforming product had efficacy outcomes that were comparable to those observed in the overall patient population.
Regarding safety, liso-cel had a favorable toxicity profile, with 60% of participants experiencing grade 3 or higher neutropenia with liso-cel. Treatment-emergent adverse effects that were grade 3 or higher included neutropenia anemia (38%) and thrombocytopenia (27%). Just under half of patients, or 42% reported any grade of cytokine release syndrome (CRS) with the product; 2% of patients experienced CRS that was grade 3 or higher.