Obecabtagene autoleucel

The safety of immunisation with live viral vaccines during or following treatment with obecabtagene autoleucel has not been studied. As a precautionary measure, vaccination with live vaccines is not recommended for at least 6 weeks prior to the start of lymphodepletion chemotherapy, during obecabtagene autoleucel treatment, and until immune recovery following treatment.

Obecabtagene autoleucel is not recommended if the patient has CD19-negative disease or an unconfirmed CD19 status.

It is not recommended that patients receive obecabtagene autoleucel within 3 months of undergoing an allogeneic haematopoietic stem cell transplantation (HSCT) because of the risk of obecabtagene autoleucel worsening GvHD.

Leukapheresis for obecabtagene autoleucel manufacturing should be performed at least 3 months after allogeneic HSCT.

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 limited experience of use of this medicinal product in patients with active CNS lymphoma defined as brain metastases confirmed by imaging. 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 obecabtagene autoleucel, however, data are limited in this population. Therefore, the benefit/risk of obecabtagene autoleucel has not been established in these populations.

There is a limited amount of data from the use of obecabtagene autoleucel in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with obecabtagene autoleucel to assess whether it can cause foetal harm when administered to a pregnant woman.

It is not known if obecabtagene 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, obecabtagene autoleucel is not recommended for women who are pregnant. Pregnant women must be advised on the potential risks to the foetus.

Pregnancy after obecabtagene autoleucel therapy must be discussed with the treating physician.

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

It is unknown whether obecabtagene autoleucel cells are excreted in human milk or transferred to the breast-feeding child. A risk to the breast-fed infant cannot be excluded. Breast-feeding women must be advised by the treating physician of the potential risk to the breast-fed child.

Women of childbearing potential / Contraception in males and females

The pregnancy status of women of childbearing potential must be verified before starting obecabtagene autoleucel treatment. Obecabtagene autoleucel is not recommended for women of childbearing potential who are not using contraception.

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

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

Fertility

There are no clinical data on the effect of obecabtagene autoleucel on fertility. Effects on male and female fertility have not been evaluated in animal studies.

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

Due to the potential for neurological events, including altered mental status or seizures, patients should refrain from driving or operating heavy or potentially dangerous machines until at least 8 weeks after infusion or until resolution of the neurological event by the treating physician.

Summary of the safety profile

The most common non-laboratory adverse reactions of any grade included CRS (68.5%), infections - pathogen unspecified (44.9%), musculoskeletal pain (31.5%), pyrexia (29.1%), pain (27.6%), nausea (26.0%), diarrhoea (25.2%), headache (23.6%), fatigue (22.0%), and haemorrhage (21.3%).

The most common non-laboratory grade 3 or higher adverse reactions were infections - pathogen unspecified (24.4%), febrile neutropenia (23.6%), viral infections (13.4%), and bacterial infectious disorders (11.0%).

The most common serious adverse reactions of any grade included infections - pathogen unspecified (20.5%), febrile neutropenia (13.4%), ICANS (9.4%), CRS (7.9%), sepsis (7.9%) and pyrexia (7.1%).

The most common grade 3 or 4 laboratory abnormalities included neutropenia (98.4%), leucocytes decreased (97.6%), lymphocytes decreased (95.3%), thrombocytopenia (77.2%), and anaemia (65.4%).

The lymphodepleting chemotherapy prior to obecabtagene autoleucel administration also contributes to the laboratory abnormalities.

Tabulated list of adverse reactions

The table below summarises the adverse reactions in a total of 127 patients exposed to obecabtagene autoleucel in the Phase Ib and Phase II FELIX study. These reactions are presented by Medical Dictionary for Regulatory Activities system organ class and by frequency. Frequencies are defined as: very common (≥1/10), and common (≥1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse drug reactions identified with obecabtagene autoleucel:

^a Frequency based on grade 3 or higher laboratory parameter.
^b Delirium includes agitation, delirium, disorientation, hallucination, irritability.
^c Encephalopathy includes aphasia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, dysarthria, dysgraphia, encephalopathy, lethargy, memory impairment, mental status changes, posterior reversible encephalopathy syndrome, somnolence.

Description of selected adverse reactions

Cytokine release syndrome

CRS was reported in 68.5% of patients, including grade 3 CRS in 2.4% of patients. The median time to onset of CRS of any grade was 8 days following the first infusion (range: 1-23 days) with a median duration of 5 days (range: 1-21 days).

In the FELIX study, 80% of patients who experienced CRS had ≥5% blasts in their BM at the time of lymphodepletion, with 39% of patients presenting with >75% blast in their BM. The most common manifestations of CRS among patients who experienced CRS included fever (68.5%), hypotension (25.2%) and hypoxia (11.8%).

The majority of patients experienced CRS after the first but prior to the second infusion of obecabtagene autoleucel. Of the 87 patients who experienced CRS, for 64.3% CRS occurred after the first, but prior to the second infusion of obecabtagene autoleucel with a median time to onset of 6 days (range: 3-9 days). Median time to onset after the second infusion was 2 days (range: 1-2 days). The primary treatment for CRS was tocilizumab (75.9%), with patients also receiving corticosteroids (22.9%) and other anti-cytokine therapies (13.8%).

Haemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS)

HLH/MAS, including severe and life-threatening reactions may occur following treatment with obecabtagene autoleucel. HLH/MAS was reported in 1.6% of patients and included grade 3 and grade 4 events with a time of onset at day 22 and day 41, respectively. One patient experienced a concurrent ICANS event after obecabtagene autoleucel infusion.

Immune effector cell-associated neurotoxicity syndrome

ICANS was reported in 29 patients (22.8%). Grade ≥ 3 ICANS occurred in 9 patients (7.1%) following treatment with obecabtagene autoleucel. One patient (1.1%) experienced grade 4 ICANS. The most common symptoms included confusional state (9.4%) and tremor (4.7%).

In the FELIX study, most patients who experienced ICANS (89.7%) and all patients who experienced grade ≥3 ICANS had >5% blasts in their BM at the time of lymphodepleting treatment. Among the patients who experienced grade ≥3 ICANS, 5 patients presented with >75% blasts in their BM.

The median time to onset for ICANS events was 12 days (range: 1-31 days) with a median duration of 8 days (range: 1-53 days). The median time to onset for ICANS events after the first infusion and before the second infusion was 8 days (range: 1-10 days) and 6.5 days (range: 2-22 days) after the second infusion. Onset of ICANS after the second infusion occurred in the majority of patients (62.1%).

Twenty-four patients received treatment for ICANS. All treated patients received high-dose corticosteroids and 12 patients received anti-epileptics prophylactically.

Prolonged cytopenia

Among the safety set (N=127), median time from day of obecabtagene autoleucel infusion to neutrophil recovery to ≥0.5 × 10⁹/L and ≥1 × 10⁹/L (based on counts at screening) was 0.8 months and 1.9 months, respectively.

Grade ≥3 cytopenias at month 1 following infusion were observed in 68.5% of patients and included neutropenia (57.5%) and thrombocytopenia (52.0%). Grade 3 or higher cytopenias at month 3 following obecabtagene autoleucel infusion was observed in 21.3% of patients and included neutropenia (13.4%) and thrombocytopenia (13.4%).

Infections

Infections following obecabtagene autoleucel infusion (all grades) occurred in 70.9% of patients. Grade 3 or 4 non-COVID-19 infections occurred in 44.9% of patients including unspecified pathogen (24.4%), bacterial (11.0%), sepsis (10.2%), viral (5.5%), and fungal (4.7%) infections.

Fatal infections of unspecified pathogen were reported in 0.8% of patients. Fatal sepsis occurred in 3.9% of patients.

Grade 3 or higher febrile neutropenia was observed in 23.6% of patients after obecabtagene autoleucel infusion and may be concurrent with CRS.

Hypogammaglobulinaemia

Hypogammaglobulinaemia was reported in 9.4% of patients, treated with obecabtagene autoleucel including 2 cases (1.6%) of grade 3 hypogammaglobulinaemia.

Immunogenicity

The humoral immunogenicity of obecabtagene autoleucel was measured using an assay for the detection of anti-drug antibodies against obecabtagene autoleucel. In the FELIX study, 8.7% of patients tested positive for anti-CD19 CAR antibodies pre-infusion. Treatment induced anti-CD19 CAR antibodies were detected in 1.6% of patients. There is no evidence that the presence of pre-existing or post-infusion anti-CD19 CAR antibodies affect the effectiveness, safety, initial expansion and persistency of obecabtagene autoleucel.

The cellular immunogenicity of obecabtagene autoleucel was measured using an enzyme-linked immunosorbent spot assay for the detection of T cell responses, measured by production of interferon gamma (IFN-γ), to the full length anti-CD19 CAR. Only 3.1% (3/96) of patients tested positive in the cellular immunogenicity readout (IFN-γ) post-infusion. There is no evidence that the cellular immunogenicity affects the kinetics of initial expansion and persistence of obecabtagene autoleucel, or the safety or effectiveness of obecabtagene autoleucel.

Secondary malignancies

There have been cases of the following adverse reaction(s) reported after treatment with other CAR T cell products, which might also occur after treatment with obecabtagene autoleucel: secondary malignancy of T cell origin.