FDA Approval Summary: Brexucabtagene Autoleucel for Treatment of Adults With Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia

Abstract

In October 2021, the FDA approved brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, for the treatment of adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (B-ALL). Approval was based on the phase II portion of ZUMA-3, a single-arm, open-label, multicenter trial that evaluated a single infusion of brexu-cel, preceded by lymphodepleting chemotherapy with cyclophosphamide and fludarabine, in this population. Efficacy was established on the basis of complete remission (CR) within 3 months after infusion and the duration of CR (DOCR). Among 54 patients in the efficacy analysis population, the CR rate was 52% (95% CI: 38, 66) with a median time-to-response of 56 days. With a median follow-up for responders of 7.1 months, the median DOCR was not reached. For all leukapheresed patients in the phase II portion of this trial (n = 71), the CR rate was 41% (95% CI: 29, 53). Among the 78 patients treated with the approved dose of brexu-cel, serious adverse reactions occurred in 79% and fatal adverse reactions occurred in 5% and included cerebral edema and infections. Cytokine release syndrome occurred in 92% (grade ≥3, 26%) and neurologic toxicities occurred in 87% (grade ≥3, 35%), leading to implementation of a risk evaluation and mitigation strategy (REMS). Postmarketing study with 15 years of follow-up will further evaluate long-term safety in adult patients with relapsed or refractory B-ALL.

Determinants of outcomes and advances in CD19‐directed chimeric antigen receptor therapy for B‐cell acute lymphoblastic leukemia

“…KTE-X19 is another CAR-T cell product which is approved in the USA (as brexucabtagene autoleucel) and in the European Union (EU) (as autologous anti-CD19-transduced CD3+ cells) in 2021 for relapsed or refractory B-ALL. 15,18 Currently, it is an approved CAR-T cell therapy for relapsed or refractory B-ALL in adults 18 years and older and the only approved CAR-T cell product in patients over age 25. The CAR protein of brexucabtagene autoleucel has a murine scFv specific to human CD19 linked to two signaling domains derived from human CD28 and CD3ζ.…”

“…In the ZUMA‐3 trial, BCA was found to be more profound in patients with CR/CRi than in patients without CR/CRi. In a study evaluating a CD19‐directed CAR‐T cell therapy (PLAT‐02) in relapsed/refractory B‐ALL, 13 at a median follow‐up duration of 9.6 months, 2–27 the median expected duration of BCA was 3 months (95% CI, 2.07–6.44). Eighteen of the 40 patients relapsed after achieving MRD‐negative CR.…”

“…Additionally, CAR‐T cell therapy is shown to produce a high rate of measurable residual disease (MRD) negative remission in 63%–93% 7–13 . The CD19‐specific CAR‐T cell therapies, Tisagenlecleucel and Brexucabtagene autoleucel have been approved by the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), Australian Therapeutic Goods Administration, and Switzerland's Swissmedic to treat relapsed/refractory B‐ALL expressing CD19 in 2017 and 2021, respectively 14,15 . The United Kingdom's Medicines and Healthcare products Regulatory Agency has designated an orphan drug status to Tisagenlecleucel and Brexucabtagene autoleucel for the treatment of B‐ALL, while the Japanese Pharmaceutical and Medical Devices Agency has approved Tisagenlecleucel only.…”

“…[7][8][9][10][11][12][13] The CD19-specific CAR-T cell therapies, Tisagenlecleucel and Brexucabtagene autoleucel have been approved by the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), Australian Therapeutic Goods Administration, and Switzerland's Swissmedic to treat relapsed/refractory B-ALL expressing CD19 in 2017 and 2021, respectively. 14,15 The United Kingdom's Medicines and Healthcare products Regulatory Agency has designated an orphan drug status to Tisagenlecleucel and Brexucabtagene autoleucel for the treatment of B-ALL, while the Japanese Pharmaceutical and Medical Devices Agency has approved Tisagenlecleucel only. CAR-T cell therapy has unique side effects, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).…”

Brexucabtagene Autoleucel (Tecartus)

“…Acute lymphoblastic leukemia (ALL) is a rare form of leukemia in adults� 1 It accounts for approximately 5% of all adult leukemia cases in Canada� Among these ALL cases, 80% are of B-cell lineage and the B-cell precursor ALL is found in 75% of adult ALL� About 50% of the patients who have B-cell precursor ALL have relapsed or refractory (R/R) disease� The estimated prevalence and incidence of R/R B-cell precursor ALL is 1,148 and 58 people, respectively, based on an estimated population in 2021 in Canada� 2 Typical clinical presentations of ALL are associated with anemia, neutropenia, and/or thrombocytopenia due to bone marrow involvement� Although more than 80% of adult patients with newly diagnosed ALL will achieve a complete remission (CR) with intensive induction chemotherapy, the majority of these patients will ultimately relapse and the prognosis is poor� 3 For patients with R/R B-cell precursor ALL, treatment options include cytotoxic chemotherapy regimens, targeted therapies, allogeneic stem cell transplant (allo-SCT) and the emerging chimeric antigen receptor T (CAR T)-cell therapy� 4,5 CAR T-cell therapy is a treatment in which T lymphocytes are removed from a patient via apheresis, transduced ex vivo with a gene rendering them immunogenic against certain cancer cells, grown, and subsequently reinfused in to the patient� The activated T-cells then circulate, attack, and kill the targeted cancer cells� 5 After the induction therapy, the patients should proceed to allo-SCT as soon as possible if they are eligible, to consolidate the treatment effect obtained from the initial induction therapy� 6 Brexucabtagene autoleucel (brexu-cel; brand name Tecartus) is a CD19-directed genetically modified autologous T-cell immunotherapy that binds to CD19-expressing cancer cells and normal B-cells� 7 On November 16, 2022, brexu-cel was approved by Health Canada for the treatment of adult patients with R/R B-cell precursor ALL� 7 The sponsor's reimbursement request is the same as the Health Canada indication� Brexu-cel is a single-dose, one-time treatment in a patient-specific infusion bag. Each patient-specific, singleinfusion bag of brexu-cel contains a suspension of anti-CD19 CAR-positive viable T-cells in approximately 68 mL for a target dose of 1 × 10 6 CAR-positive viable T-cells per kg of body weight, with a maximum of 1 × 10 8 CAR-positive viable T-cells for patients weighing 100 kg or more� 7…”