Lisocabtagene maraleucel receives FDA approval for its first indication in patients with large B-cell lymphoma.
The FDA has issued an approval to the biologics license application (BLA) for the CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (Breyanzi; liso-cel) in the treatment of adult patients with certain types of large B-cell lymphoma following 2 or more prior therapies.1
Liso-cel targets CD19 expression through a CAR construct comprised of a 4-1BB costimulatory domain for T-cell propagation and preservation, and a CD3-z T-cell activation domain, and an anti-CD19 single-chain variable fragment–targeting domain for antigen specificity.
“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. “Gene and cell therapies have evolved from promising concepts to practical cancer treatment regimens.”
Efficacy of liso-cel in patients with relapsed or refractory large B-cell lymphomas is supported by results of the phase 1 TRANSCEND NHL 001 trial (NCT02631044) that were published in The Lancet in 2020.2 Of 256 patients evaluable for efficacy, 186 (73%; 95% CI, 66.8%-78.0%) achieved an objective response, of whom 136 (53%; 95% CI, 46.8%-59.4%) had a complete response. At the time of data cutoff, the duration of response had not been reached with rates at 6 and 12 months of 60.4% (95% CI, 52.6%-67.3%) and 54.7% (95% CI, 46.7%-62.0%), respectively.
The most common grade 3 or high adverse effects were neutropenia (60%), anemia (37%), and thrombocytopenia (27%). Cytokine release syndrome (CRS) occurred in 42% of patients, with only 2% of patients having grade 3 or worse CRS. Neurologic events occurred at rates of 30% and 10%, respectively. Nine patients (6%) had dose-limiting toxicities.
Overall, safety and activity of liso-cel did not appear to be dose dependent, and the recommended target dose based on the data was 100 × 106 CAR-positive T-cells.
The approval follows a long investigation process by the FDA, extending several months past the initial target action date of August 17, 2020 that was assigned to the BLA upon acceptance and priority review designation in early 2020.3 Travel restrictions due to the coronavirus disease 2019 (COVID-19) pandemic that prevented timely conduct of inspections of third-party manufacturing facilities are among the reasons for a delay in approval.
Liso-cel was previously granted breakthrough therapy designation and Regenerative Medicine Advanced Therapy designation by the FDA for various B-cell lymphomas. In May 2020, the FDA pushed the originally set Prescription Drug User Fee Act date from August to November 16, 2020 based on new information submitted to fulfill an agency request that was deemed to be a major amendment to the application.4 In November, Bristol Myers Squibb again announced that the PDUFA date would not be met, this time based on aforementioned travel restrictions, and no new date for approval was assigned.5
When liso-cel failed to gain approval by December 31, 2021, 1 of 3 preset milestones required for payment of the Bristol Myers Squibb Contingent Value Rights (CVR) agreement was not met. As a result, automatic termination of the CVR occurred and these securities were no longer eligible for payment.6
1. FDA Approves New Treatment For Adults With Relapsed Or Refractory Large-B-Cell Lymphoma. News release. February 5, 2021. Accessed February 5, 2021. https://prnmedia.prnewswire.com/news-releases/fda-approves-new-treatment-for-adults-with-relapsed-or-refractory-large-b-cell-lymphoma-301223275.html
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. Lancet. 2020;396(10254):839-852. doi: 10.1016/S0140-6736(20)31366-0
3. U.S. Food and Drug Administration (FDA) accepts for priority review Bristol-Myers Squibb’s biologics license application (BLA) for lisocabtagene maraleucel (liso-cel) for adult patients with relapsed or refractory large B-cell lymphoma. Bristol Myers Squibb. February 13, 2020. Accessed January 25, 2021. https://bit.ly/36cisOW
4. Bristol Myers Squibb provides update on biologics license application (BLA) for lisocabtagene maraleucel (liso-cel). Bristol Myers Squibb. May 6, 2020. Accessed January 25, 2021. https://bit.ly/369ucBy
5. Bristol Myers Squibb provides regulatory update on lisocabtagene maraleucel (liso-cel). Bristol Myers Squibb. November 16, 2020. Accessed January 25, 2021. https://bit.ly/39Y6zNA
6. Bristol Myers Squibb statement on status of liso-cel application and contingent value rights. Bristol Myers Squibb. November 1, 2020. Accessed January 25, 2021. https://bit.ly/2MrD4vi