Lisocabtagene maraleucel

The safety of immunisation with live viral vaccines during or following treatment with lisocabtagene maraleucel 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 lymphodepleting chemotherapy, during lisocabtagene maraleucel treatment, and until immune recovery following treatment.

There is no clinical experience in patients with severe renal impairment (creatinine clearance ≤30 mL/min).

Long-term persistence of CAR T cells may be affected by the subsequent use of anti-EGFR mabs however, there is limited information available on the clinical use of anti-EGFR mabs in patients treated with lisocabtagene maraleucel.

It is not recommended that patients who underwent an allogeneic stem cell transplant and suffer from active acute or chronic GVHD receive treatment because of the potential risk of lisocabtagene maraleucel worsening GVHD.

Lisocabtagene maraleucel should not be administered to patients with a clinically significant active infection or inflammatory disorder.

There is no clinical experience in patients with active HIV, HBV or HCV infection. Screening for HIV, active HBV and active HCV must be performed before collection of cells for manufacturing. Leukapheresis material from patients with active HIV or active HCV infection will not be accepted for manufacturing.

There are no data from the use of lisocabtagene maraleucel in pregnant women. No animal reproductive and developmental toxicity studies have been conducted to assess whether it can cause foetal harm when administered to a pregnant woman.

It is not known if lisocabtagene maraleucel 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, lisocabtagene maraleucel 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 lisocabtagene maraleucel therapy should be discussed with the treating physician.

Assessment of immunoglobulin levels and B-cells in newborns of mothers treated with should be considered.

It is unknown whether lisocabtagene maraleucel is excreted in human milk or transferred to the breast-feeding child. Women who are breast-feeding should be advised of the potential risk to the breast-fed child.

Women of childbearing potential/Contraception in males and females

Pregnancy status for women of child-bearing potential should be verified using a pregnancy test prior to starting treatment with lisocabtagene maraleucel.

See the prescribing information for fludarabine and cyclophosphamide 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 lisocabtagene maraleucel.

Fertility

There are no data on the effect of lisocabtagene maraleucel on fertility.

Lisocabtagene maraleucel may have major influence on the ability to drive and use machines.

Due to the potential for neurologic events, including altered mental status or seizures with lisocabtagene maraleucel, patients receiving lisocabtagene maraleucel should refrain from driving or operating heavy or potentially dangerous machines for at least 8 weeks after lisocabtagene maraleucel infusion.

Summary of the safety profile

Patients who received one prior line of therapy for LBCL

The adverse reactions described in this section were characterised in 177 patients infused with lisocabtagene maraleucel from 3 pooled studies TRANSFORM [BCM-003], PILOT ⁰¹⁷⁰⁰⁶, and TRANSCEND WORLD [JCAR017-BCM-001, cohort 2].

The most common adverse reactions of any grade were neutropenia (71%), anaemia (45%), CRS (45%), and thrombocytopenia (43%).

The most common serious adverse reactions were CRS (12%), neutropenia (3%), bacterial infectious disorders (3%), infection with an unspecified pathogen (3%), thrombocytopenia (2%), febrile neutropenia (2%), pyrexia (2%), aphasia (2%), headache (2%), confusional state (2%), pulmonary embolism (2%), anaemia (1%), upper gastrointestinal haemorrhage (1%), and tremor (1%).

The most common Grade 3 or higher adverse reactions included neutropenia (68%), thrombocytopenia (33%), anaemia (31%), lymphopenia (17%), leukopenia (17%), febrile neutropenia (5%), and bacterial infections (5%).

Patients who received two or more prior lines of therapy for LBCL

The adverse reactions described in this section were characterised in 384 patients infused with lisocabtagene maraleucel from 4 pooled studies (TRANSCEND ⁰¹⁷⁰⁰¹, TRANSCEND WORLD [JCAR017-BCM-001, cohort 1, 3 and 7], PLATFORM [JCAR017-BCM-002] and OUTREACH ⁰¹⁷⁰⁰⁷.

The most common adverse reactions of any grade were neutropenia (68%), anaemia (45%), CRS (38%), fatigue (37%), and thrombocytopenia (36%).

The most common serious adverse reactions were CRS (18%), infection with an unspecified pathogen (6%), pyrexia (4%), encephalopathy (4%), febrile neutropenia (4%), neutropenia (3%), thrombocytopenia (3%), aphasia (3%), bacterial infectious disorders (3%), tremor (3%), confusional state (3%), anaemia 2% and hypotension (2%).

The most common Grade 3 or higher adverse reactions included neutropenia (64%), anaemia (34%), thrombocytopenia (29%), leukopenia (25%), lymphopenia (9%), infection with an unspecified pathogen (8%) and febrile neutropenia (8%).

Tabulated list of adverse reactions

The frequencies of adverse reactions are based on pooled data from 6 studies (TRANSCEND ⁰¹⁷⁰⁰¹, TRANSCEND WORLD [JCAR017-BCM-001, cohort 1, 2, 3 and 7], PLATFORM [JCAR017-BCM-002], OUTREACH ⁰¹⁷⁰⁰⁷, TRANSFORM [BCM-003], and PILOT ⁰¹⁷⁰⁰⁶), in 561 adult patients and from post-marketing reports within the dose range of 44-120 × 10⁶ CAR-positive viable T cells with R/R LBCL, defined as DLBCL, HGBCL, PMBCL and FL3B, who received a dose of lisocabtagene maraleucel. The adverse reaction frequencies from clinical studies are based on all-cause adverse event frequencies, where a proportion of the events for an adverse reaction may have other causes.

Adverse reactions reported are presented below. These reactions are presented by MedDRA system organ class and by frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Adverse drug reactions identified with lisocabtagene maraleucel:

^* Event was not systematically collected in clinical trials.
^a Infections and infestations are grouped per MedDRA high level group term
^b Delirium includes agitation, delirium, delusion, disorientation, hallucination, hallucination visual, irritability, restlessness
^c Headache includes headache, migraine, migraine with aura, sinus headache
^d Encephalopathy includes amnesia, cognitive disorder, confusional state, depersonalisation/derealisation disorder, depressed level of consciousness, disturbance in attention, encephalopathy, flat affect, lethargy, leukoencephalopathy, loss of consciousness, memory impairment, mental impairment, mental status changes, paranoia, somnolence, stupor
^e Dizziness includes dizziness, dizziness postural, presyncope, syncope
^f Tremor includes essential tremor, intention tremor, resting tremor, tremor
^g Aphasia includes aphasia, disorganised speech, dysarthria, dysphonia, slow speech
^h Peripheral neuropathy includes demyelinating polyneuropathy, hyperaesthesia, hypoaesthesia, hyporeflexia, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral sensory neuropathy, sensory loss
ⁱ Visual disturbance includes blindness, blindness unilateral, gaze palsy, mydriasis, nystagmus, vision blurred, visual field defect, visual impairment
^j Ataxia includes ataxia, gait disturbance
^k Taste disorder includes dysgeusia, taste disorder
^l Cerebellar syndrome includes balance disorder, dysdiadochokinesis, dyskinesia, dysmetria, hand-eye coordination impaired
^m Cerebrovascular disorder includes cerebral infarction, cerebral venous thrombosis, haemorrhage intracranial, transient ischaemic attack
ⁿ Seizure includes seizure, status epilepticus
° Arrhythmia includes arrhythmia, atrial fibrillation, atrioventricular block complete, atrioventricular block second degree, supraventricular tachycardia, ventricular tachycardia
^p Thrombosis includes deep vein thrombosis, embolism, embolism venous, pulmonary embolism, thrombosis, vena cava thrombosis, venous thrombosis, venous thrombosis limb
^q Dyspnoea includes acute respiratory failure, dyspnoea, dyspnoea exertional, respiratory failure.
^r Gastrointestinal haemorrhage includes gastric haemorrhage, gastric ulcer haemorrhage, gastrointestinal haemorrhage, haematochezia, lower gastrointestinal haemorrhage, melaena, rectal haemorrhage, upper gastrointestinal haemorrhage
^s Acute kidney injury includes acute kidney injury, blood creatinine increased, glomerular filtration rate decreased, renal failure, renal impairment, renal injury
^t Oedema includes generalised oedema, localised oedema, oedema, oedema genital, oedema peripheral, peripheral swelling, scrotal oedema, swelling.

Description of selected adverse reactions

Cytokine release syndrome

For patients who received one prior line of therapy for LBCL, CRS occurred in 45% of patients, 1% of whom experienced Grade 3 CRS (no fatal events). The median time to onset was 4 days (range: 1 to 63 days, with the upper limit due to CRS onset, without fever, reported in one patient) and the median duration of CRS was 4 days (range: 1 to 16 days).

The most common manifestations of CRS included pyrexia (44%), hypotension (12%), chills (5%), hypoxia (5%), tachycardia (4%), headache (3%), and fatigue (2%).

In clinical studies, 42 of 177 (24%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of lisocabtagene maraleucel. Eighteen (10%) patients received tocilizumab only, 24 (14%) patients received tocilizumab and a corticosteroid and no patients received corticosteroids only.

For patients who received two or more prior lines of therapy for LBCL, CRS occurred in 38% of patients, 2% of whom experienced Grade 3 or 4 (severe or life-threatening) CRS. There were no fatal events. Among patients who died after receiving lisocabtagene maraleucel, 4 had ongoing CRS events at the time of death. The median time to onset was 4 days (range: 1 to 14 days) and the median duration was 5 days (range: 1 to 17 days).

The most common manifestations of CRS included pyrexia (38%), hypotension (18%), tachycardia (13%), chills (9%), and hypoxia (8%).

In clinical studies, 74 of 384 (19%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of lisocabtagene maraleucel. Thirty-seven (10%) patients received tocilizumab only, 29 (8%) received tocilizumab and a corticosteroid and 8 (2%) received corticosteroids only.

Neurologic adverse reactions

For patients who received one prior line of therapy for LBCL, CAR T cell-associated neurologic toxicities, assessed by the investigator, occurred in 18% of patients receiving lisocabtagene maraleucel, including Grade 3 in 5% of patients (no fatal events). The median time to onset of the first event was 8 days (range: 1 to 63 days); 97% of all neurologic toxicities occurred within the first 8 weeks following lisocabtagene maraleucel infusion. The median duration of neurologic toxicities was 6 days (range: 1 to 89 days).

The most common neurologic toxicities included encephalopathy (10%), tremor (8%), aphasia (5%), dizziness (2%), and headache (1%).

For patients who received two or more prior lines of therapy for LBCL, CAR T cell-associated neurologic toxicities assessed by the investigator occurred in 26% of patients receiving lisocabtagene maraleucel, including Grade 3 or 4 in 10% of patients (no fatal events). The median time to onset of the first event was 9 days (range: 1 to 66 days); 99% of all neurologic toxicities occurred within the first 8 weeks following lisocabtagene maraleucel infusion. The median duration of neurologic toxicities was 10 days (range: 1 to 84 days).

The most common neurologic toxicities included encephalopathy (18%), tremor (9%), aphasia (8%), delirium (7%), headache (4%), ataxia (3%) and dizziness (3%). Seizures (2%) and cerebral oedema (0.3%) have also occurred in patients treated with lisocabtagene maraleucel.

There have been reports of fatal events of ICANS in the post-marketing setting.

Febrile neutropenia and infections

Febrile neutropenia has been observed in 7% of patients after receiving lisocabtagene maraleucel who received one prior line of therapy for LBCL and 9% of patients after receiving lisocabtagene maraleucel who received two or more prior lines of therapy.

For patients who received one prior line of therapy for LBCL, infections (all grades) occurred in 25% of patients. Grade 3 or higher infections occurred in 10% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 3% of patients, bacterial infections occurred in 5%, and viral and fungal infections occurred in 2% and none of patients, respectively.

For patients who received two or more prior lines of therapy for LBCL, infections (all grades) occurred in 38% of patients. Grade 3 or higher infections occurred in 12% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 8% of patients, bacterial infections occurred in 4% of patients, viral and fungal infections occurred in 1% of patients.

Opportunistic infections (all grades) have been observed in 2% of the 177 patients treated with lisocabtagene maraleucel who received one prior line of therapy for LBCL, with Grade 3 or higher opportunistic infections having occurred in 1% of patients. Opportunistic infections (all grades) have been observed in 3% of the 384 patients treated with lisocabtagene maraleucel who received two or more prior lines of therapy for LBCL, with Grade 3 or higher opportunistic infections having occurred in 1% of patients.

No fatal infections were reported from the 177 patients treated with lisocabtagene maraleucel who received one prior line of therapy for LBCL. Four fatal infections were reported from the 384 patients treated with lisocabtagene maraleucel who received two or more prior lines of therapy for LBCL among pooled LBCL studies. Of these, 1 was reported as a fatal opportunistic infection.

Prolonged cytopenias

For patients who received one prior line of therapy for LBCL, Grade 3 or higher cytopenias present at Day 35 following lisocabtagene maraleucel administration, occurred in 35% of patients, and included thrombocytopenia (28%), neutropenia (26%), and anaemia (9%).

Of the 177 total patients treated in TRANSFORM, PILOT, and TRANSCEND WORLD (cohort 2) who had Day 35 laboratory findings of Grade 3-4 thrombocytopenia (n=50) or Grade 3-4 neutropenia (n=26) or Grade 3-4 anaemia (n=15), for whom follow-up laboratory cytopenia results were available, the median time (min, max) to resolution (cytopenia recovering to Grade 2 or less) was as follows in days: thrombocytopenia 31 days (4, 309); neutropenia 31 days (17, 339); and anaemia 22 days (4, 64).

For patients who received two or more prior lines of therapy for LBCL, Grade 3 or higher cytopenias present at Day 29 following lisocabtagene maraleucel administration, occurred in 38% of patients, and included thrombocytopenia (31%), neutropenia (21%) and anaemia (7%).

Of the 384 total patients treated in TRANSCEND, TRANSCEND WORLD (Cohort 1, 3, and 7), PLATFORM, and OUTREACH who had Day 29 laboratory findings of Grade 3-4 thrombocytopenia (n=117) or Grade 3-4 neutropenia (n=80) or Grade 3-4 anaemia (n=27), for whom follow-up laboratory cytopenia results were available, the median time (min, max) to resolution (cytopenia recovering to Grade 2 or less) was as follows in days: thrombocytopenia 30 days (2, 329); neutropenia 29 days (3, 337); and anaemia 15 days (3, 78).

Hypogammaglobulinaemia

For patients who received one prior line of therapy for LBCL, adverse events of hypogammaglobulinemia occurred in 7% of patients. For patients who received two or more prior line of therapy for LBCL, adverse events of hypogammaglobulinaemia occurred in 11% of patients.

Immunogenicity

Lisocabtagene maraleucel has the potential to induce antibodies against this medicinal product. Humoral immunogenicity of lisocabtagene maraleucel was measured by determination of anti-CAR antibody pre- and post- administration. In patients who received one prior line of therapy for LBCL (TRANSFORM, PILOT and TRANSCEND WORLD, cohort 2), pre-existing anti-therapeutic antibodies (ATAs) were detected in 0.6% (1/169) of patients, and treatment-induced ATAs were detected in 4% (7/168) of patients. In the pooled studies for patients who received two or more prior lines of therapy for LBCL (TRANSCEND and TRANSCEND WORLD, cohort’s 1 and 3), pre-existing ATAs were detected in 9% (29/309) of patients, and treatment-induced or treatment-boosted ATAs were detected in 16% (48/304) of patients. The relationships between ATA status and efficacy, safety or pharmacokinetics were not conclusive due to the limited number of patients with ATAs.