Brexucabtagene autoleucel

In immunosuppressed patients, life-threatening and fatal opportunistic infections including disseminated fungal infections and viral reactivation (e.g., HHV-6 and progressive multifocal leukoencephalopathy) have been reported. The possibility of these infections should be considered in patients with neurologic events and appropriate diagnostic evaluations must be performed.

Prophylactic use of systemic corticosteroids may interfere with the activity of brexucabtagene autoleucel. Prophylactic use of systemic corticosteroids is therefore not recommended before infusion.

Administration of corticosteroids as per the toxicity management guidelines does not impact the expansion and persistence of CAR T cells.

Patients with a history of or active CNS disorder or inadequate renal, hepatic, pulmonary, or cardiac function were excluded from the studies. These patients are likely to be more vulnerable to the consequences of the adverse reactions described below and require special attention.

There is no experience of use of this medicinal product in patients with active CNS lymphoma defined as brain metastases confirmed by imaging. In ALL, asymptomatic patients with a maximum of CNS-2 disease (defined as white blood cells <5/µL in cerebral spinal fluid with presence of lymphoblasts) without clinically evident neurological changes were treated with brexucabtagene autoleucel, however, data is limited in this population. Therefore, the benefit/risk of brexucabtagene autoleucel has not been established in these populations.

There is no experience with manufacturing brexucabtagene autoleucel for patients with a positive test for HIV, active HBV, or active HCV infection. Therefore, the benefit/risk has not yet been established in this population.

There are no available data with brexucabtagene autoleucel use in pregnant women. No reproductive and developmental toxicity animal studies have been conducted with brexucabtagene autoleucel to assess whether it can cause foetal harm when administered to a pregnant woman.

It is not known if brexucabtagene autoleucel has the potential to be transferred to the foetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause foetal toxicity, including B-cell lymphocytopenia. Therefore, brexucabtagene autoleucel is not recommended for women who are pregnant, or for women of childbearing potential not using contraception. Pregnant women should be advised on the potential risks to the foetus. Pregnancy after brexucabtagene autoleucel therapy should be discussed with the treating physician.

Assessment of immunoglobulin levels and B-cells in newborn infants of mothers treated with brexucabtagene autoleucel must be considered.

It is unknown whether brexucabtagene autoleucel is excreted in human milk or transferred to the breast-feeding child.

Breast-feeding women must be advised of the potential risk to the breast-fed child.

Women of childbearing potential/Contraception

The pregnancy status of women of childbearing potential must be verified before starting brexucabtagene autoleucel treatment.

See the prescribing information for lymphodepleting chemotherapy for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy.

There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with brexucabtagene autoleucel.

Fertility

No clinical data on the effect of brexucabtagene autoleucel on fertility are available. Effects on male and female fertility have not been evaluated in animal studies.

Brexucabtagene autoleucel has major influence on the ability to drive and use machines.

Due to the potential for neurologic events, including altered mental status or seizures, patients must not drive or operate heavy or potentially dangerous machines until at least 8 weeks after infusion or until resolution of neurologic adverse reactions.

Summary of the safety profile

Mantle cell lymphoma

The safety data described in this section reflect exposure to brexucabtagene autoleucel in ZUMA-2, a Phase 2 study in which a total of 82 patients with relapsed/refractory MCL received a single dose of CAR-positive viable T cells (2 × 10⁶ or 0.5 × 10⁶ anti-CD19 CAR T cells/kg) based on a recommended dose which was weight-based.

The most significant and frequently occurring adverse reactions were CRS (91%), infections (55%) and encephalopathy (51%).

Serious adverse reactions occurred in 56% of patients. The most common serious adverse reactions included encephalopathy (26%), infections (28%) and cytokine release syndrome (15%).

Grade 3 or higher adverse reactions were reported in 67% of patients. The most common Grade 3 or higher non-haematological adverse reactions included infections (34%) and encephalopathy (24%). The most common Grade 3 or higher haematological adverse reactions included neutropenia (99%), leukopenia (98%), lymphopenia (96%), thrombocytopenia (65%) and anaemia (56%).

Acute lymphoblastic leukaemia

The safety data described in this section reflect exposure to brexucabtagene autoleucel in ZUMA-3, a Phase ½ study in which a total of 100 patients with relapsed/refractory B-cell precursor ALL received a single dose of CAR-positive viable T cells (0.5 × 10⁶, 1 × 10⁶, or 2 × 10⁶ anti-CD19 CAR T cells/kg) based on a recommended dose which was weight based.

The most significant and frequently occurring adverse reactions were CRS (91%), encephalopathy (57%), and infections (41%).

Serious adverse reactions occurred in 70% of patients. The most common serious adverse reactions included CRS (25%), infections (22%) and encephalopathy (21%).

Grade 3 or higher adverse reactions were reported in 76% of patients. The most common Grade 3 or higher non-haematological adverse reactions included infections (27%), CRS (25%) and encephalopathy (22%).

Tabulated list of adverse reactions

Adverse reactions described in this section were identified in a total of 182 patients exposed to brexucabtagene autoleucel in two multi-centre pivotal clinical studies, ZUMA-2 (n=82) and ZUMA-3 (n=100). These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Adverse drug reactions identified with brexucabtagene autoleucel:

Only cytopenias that resulted in (i) new or worsening clinical sequelae or (ii) that required therapy or (iii) adjustment in current therapy are included in the table.
^a Frequency based on Grade 3 or higher laboratory parameter.
^b See section Description of selected adverse reactions.
ZUMA-2 data cutoff: 24 July 2021; ZUMA-3 data cutoff: 23 July 2021

Description of selected adverse reactions from ZUMA-2 and ZUMA-3 (n=182)

Cytokine release syndrome

CRS occurred in 91% of patients. Twenty percent (20%) of patients experienced Grade 3 or higher (severe or life-threatening) CRS. The median time to onset was 3 days (range: 1 to 13 days) and the median duration was 9 days (range: 1 to 63 days). Ninety-seven percent (97%) of patients recovered from CRS.

The most common signs or symptoms associated with CRS among the patients who experienced CRS included pyrexia (94%), hypotension (64%), hypoxia (32%), chills (31%), tachycardia (27%), sinus tachycardia (23%), headache (22%), fatigue (16%), and nausea (13%). Serious adverse reactions that may be associated with CRS included hypotension (22%), pyrexia (15%), hypoxia (9%), tachycardia (3%), dyspnoea (2%) and sinus tachycardia (2%).

Neurologic events and adverse reactions

Neurologic adverse reactions occurred in 69% of patients. Thirty-two percent (32%) of patients experienced Grade 3 or higher (severe or life-threatening) adverse reactions. The median time to onset was 7 days (range: 1 to 262 days). Neurologic events resolved for 113 out of 125 patients (90.4%) with a median duration of 12 days (range: 1 to 708 days). Three patients had ongoing neurologic events at the time of death, including one patient with the reported event of serious encephalopathy and another patient with the reported event of serious confusional state. The remaining unresolved neurologic events were Grade 2. Ninety-three percent of all treated patients experienced the first CRS or neurological event within the first 7 days after brexucabtagene autoleucel infusion.

The most common neurologic adverse reactions included tremor (32%), confusional state (27%), encephalopathy (27%), aphasia (21%), and agitation (11%). Serious adverse reactions including encephalopathy (15%), aphasia (6%) and confusional state (5%) have been reported in patients administered brexucabtagene autoleucel. ICANS was reported as a serious adverse neurologic reaction at a low frequency (2%) in clinical trials. ICANS observed during clinical studies are represented under the adverse reaction encephalopathy. Serious cases of cerebral oedema which may become fatal have occurred in patients treated with brexucabtagene autoleucel.

ICANS was reported in the context of neurologic toxicity in the post marketing setting.

Febrile neutropenia and infections

Febrile neutropenia was observed in 12% of patients after brexucabtagene autoleucel infusion. Infections occurred in 87 of the 182 patients treated with brexucabtagene autoleucel in ZUMA-2 and ZUMA-3. Grade 3 or higher (severe, life-threatening or fatal) infections occurred in 30% of patients including unspecified pathogen, bacterial, fungal and viral infections in 23%, 8%, 2% and 4% of patients respectively.

Prolonged cytopenias

Cytopenias are very common following prior lymphodepleting chemotherapy and brexucabtagene autoleucel therapy.

Prolonged (present on or beyond Day 30 or with an onset at Day 30 or beyond) Grade 3 or higher cytopenias occurred in 48% of patients and included neutropenia (34%), thrombocytopenia (27%) and anaemia (15%).

Hypogammaglobulinaemia

Hypogammaglobulinaemia occurred in 12% of patients. Grade 3 or higher hypogammaglobulinemia occurred in 1% of patients.

Immunogenicity

The immunogenicity of brexucabtagene autoleucel has been evaluated using an enzyme-linked immunosorbent assay (ELISA) for the detection of binding antibodies against FMC63, the originating antibody of the anti-CD19 CAR. To date, no anti-CD19 CAR T-cell antibody immunogenicity has been observed in MCL patients. Based on an initial screening assay, 17 patients in ZUMA-2 at any time point tested positive for antibodies; however, a confirmatory orthogonal cell-based assay demonstrated that all 17 patients in ZUMA-2 were antibody negative at all time points tested. Based on an initial screening assay, 16 patients in ZUMA-3 tested positive for antibodies at any timepoint. Among patients with evaluable samples for confirmatory testing, two patients were confirmed to be antibody-positive after treatment. One of the two patients had a confirmed positive antibody result at Month 6. The second patient had a confirmed positive antibody result at retreatment Day 28 and Month 3. There is no evidence that the kinetics of initial expansion, CAR T-cell function and persistence of brexucabtagene autoleucel, or the safety or effectiveness of brexucabtagene autoleucel, were altered in these patients.