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 4 weeks after lisocabtagene maraleucel infusion, or longer at the physician's discretion.

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%).

FL

The adverse reactions described in this section were characterised in 130 patients infused with lisocabtagene maraleucel from study TRANSCEND-FL (FOL-001).

The most common adverse reactions of any grade were neutropenia (68%), CRS (58%), anaemia (40%), headache (29%), thrombocytopenia (29%) and constipation (21%).

The most common serious adverse reactions were CRS (9%), aphasia (4%), febrile neutropenia (3%), pyrexia (2%) and tremor (2%).

The most common Grade 3 or higher adverse reactions included neutropenia (61%), leukopenia (12%), lymphopenia (12%), thrombocytopenia (12%) and anaemia (10%).

MCL

The adverse reactions described in this section were characterised in 88 patients infused with lisocabtagene maraleucel from study TRANSCEND-MCL Cohort [017001].

The most common adverse reactions of any grade were CRS (61%), neutropenia (59%), anaemia (44%), fatigue (35%), thrombocytopenia (30%), and headache (23%).

The most common serious adverse reactions were CRS (24%), confusional state (6%), pyrexia (3%), mental status changes (2%), encephalopathy (2%), upper respiratory tract infection (2%), and pleural effusion (2%).

The most common Grade 3 or higher adverse reactions included neutropenia (56%), anaemia (38%), thrombocytopenia (25%), hypophosphataemia (9%), and leukopenia (7%).

Tabulated list of adverse reactions

The frequencies of adverse reactions are based on pooled data from 7 studies (TRANSCEND [017001], including LBCL and MCL Cohorts, TRANSCEND WORLD [JCAR017-BCM-001, Cohort 1, 2, 3 and 7], PLATFORM [JCAR017-BCM-002], OUTREACH [017007], TRANSFORM [BCM-003], PILOT [017006] and TRANSCEND-FL (JCAR017-FOL-001), in 779 adult patients and from post-marketing reports 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, ophthalmic migraine, 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, speech disorder
^h Peripheral neuropathy includes demyelinating polyneuropathy, hyperaesthesia, hyp oaesthesia, hyporeflexia, loss of proprioception, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral sensory neuropathy, sensory loss, carpal tunnel syndrome
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 sinus thrombosis, embolic cerebral infarction, haemorrhage intracranial, transient ischaemic attack
ⁿ Seizure includes seizure, status epilepticus
° Paresis includes facial paralysis, facial paresis, vocal cord paralysis
^p Arrhythmia includes arrhythmia, atrial fibrillation, atrioventricular block complete, atrioventricular block second degree, supraventricular tachycardia, extrasystoles,ventricular extrasystoles, ventricular tachycardia
^q Thrombosis includes deep vein thrombosis, embolism, pulmonary embolism, thrombosis, vena cava thrombosis, venous thrombosis, venous thrombosis limb
^r Dyspnoea includes acute respiratory failure, dyspnoea, dyspnoea exertional, respiratory failure.
^s Gastrointestinal haemorrhage includes gastric haemorrhage, gastric ulcer haemorrhage, gastrointestinal haemorrhage, haematochezia, lower gastrointestinal haemorrhage, melaena, rectal haemorrhage, upper gastrointestinal haemorrhage
^t Acute kidney injury includes acute kidney injury, blood creatinine increased, glomerular filtration rate decreased, renal failure, renal impairment, renal injury
^u Oedema includes face oedema, generalised oedema, localised oedema, oedema, oedema genital, oedema peripheral, peripheral swelling, scrotal oedema, swelling, swelling face.
^v Hypogammaglobulinemia includes blood immunoglobulin A decreased, blood immunoglobulin G decreased, blood immunoglobulin M decreased, hypogammaglobulinaemia, immunoglobulins decreased.
^w Hypofibrinogenaemia includes blood fibrinogen decreased, hypofibrinogenaemia

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. 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. 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 LBCL 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.

For patients who received lisocabtagene maraleucel for FL, CRS occurred in 58% of patients, 0.8% of whom experienced Grade 3 CRS. The median time to onset was 6 days (range: 1 to 17 days) and the median duration of CRS was 3 days (range: 1 to 10 days).

The most common manifestations of CRS included pyrexia (57%), hypotension (14%), chills (4%) hypoxia (2%) and tachycardia (0.8%).

In the FL clinical study, 33 of 130 (25%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of lisocabtagene maraleucel. Eighteen (14%) patients received tocilizumab only, 15 (12%) received tocilizumab and a corticosteroid and no patients received corticosteroids only.

For patients who received lisocabtagene maraleucel for MCL, CRS occurred in 61% of patients, 1% of whom experienced Grade 3 or 4 CRS. The median time to onset was 4 days (range: 1 to 10 days) and the median duration of CRS was 4 days (range: 1 to 14 days).

The most common manifestations of CRS included pyrexia (60%), hypotension (22%), hypoxia (11%) tachycardia (10%), chills (8%), headache (8%), nausea (3%), and dyspnoea (2%).

In the TRANSCEND-MCL Cohort, 24 of 88 (27%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of lisocabtagene maraleucel. 15 (17%) patients received tocilizumab only, 8 (9%) received tocilizumab and a corticosteroid and 1 (1%) patient 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. The median time to onset of the first event was 8 days (range: 1 to 63 days); 84% of all neurologic toxicities occurred within 2 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. The median time to onset of the first event was 9 days (range: 1 to 66 days); 83% of all neurologic toxicities occurred within 2 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.

For patients who received lisocabtagene maraleucel for FL, CAR T-cell-associated neurologic toxicities, assessed by the investigator, occurred in 16% of patients receiving lisocabtagene maraleucel, including Grade 3 in 3% of patients. The median time to onset of the first event was 8 days (range: 4 to 16 days); 95% of all neurologic toxicities occurred within 2 weeks following lisocabtagene maraleucel infusion. The median duration of neurologic toxicities was 3 days (range: 1 to 17 days).

The most common neurologic toxicities included tremor (8%), aphasia (8%), encephalopathy (5%), delirium (4%) and headache (2%).

For patients who received lisocabtagene maraleucel for MCL, CAR T-cell-associated neurologic toxicities, assessed by the investigator, occurred in 31% of patients receiving lisocabtagene maraleucel, including Grade 3 or 4 in 9% of patients. The median time to onset of the first event was 8 days (range: 1 to 25 days); 100% of all neurologic toxicities occurred within the first 8 weeks following lisocabtagene maraleucel infusion. The median duration of neurologic toxicities was 5 days (range: 1 to 45 days).

The most common neurologic toxicities included encephalopathy (26%), tremor (7%), delirium (6%), aphasia (6%), headache (5%), and dizziness (3%). Seizures (1%) have 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% and 9% of patients who received lisocabtagene maraleucel for LBCL after one prior line of therapy and two or more prior lines of therapy, respectively, in 5% of patients who received lisocabtagene maraleucel for FL and in 6% of patients after receiving lisocabtagene maraleucel for MCL.

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.

For patients who received lisocabtagene maraleucel for FL, infections (all grades) occurred in 20% of patients. Grade 3 occurred in 5% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 4% of patients, bacterial infections occurred in 2% of patients, viral and fungal infections occurred in 1% and none of patients, respectively.

For patients who received lisocabtagene maraleucel for MCL, infections (all grades) occurred in 35% of patients. Grade 3 or higher occurred in 15% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 6% of patients, bacterial infections occurred in 5% of patients, viral and fungal infections occurred in 5% and 1% of patients, respectively.

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 0.6% 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. Opportunistic infections (all grades) have been observed in 0.8% of the 130 patients treated with lisocabtagene maraleucel who received lisocabtagene maraleucel for FL, with no Grade 3 or higher opportunistic infections observed. Opportunistic infections (all grades) have been observed in 1% of the 88 patients who received lisocabtagene maraleucel for MCL, all of which were Grade 3 or higher.

Two 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. No fatal infections were reported in the 130 patients treated with lisocabtagene maraleucel for FL. Two fatal infections were reported in the 88 patients treated with lisocabtagene maraleucel for MCL.

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 respectively Day 35 and Day 29 laboratory findings of Grade 3-4 thrombocytopenia (n=50) or Grade 3-4 neutropenia (n=46) 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 32 days (4, 309); neutropenia 32 days (8, 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).

For patients who received lisocabtagene maraleucel for FL, Grade 3 or higher cytopenias present at Day 29 following lisocabtagene maraleucel administration, occurred in 22% of patients, and included thrombocytopenia (15%), neutropenia (15%) and anaemia (5%). Of the 130 total patients treated in TRANSCEND FL who had Day 29 laboratory findings of Grade 3-4 thrombocytopenia (n=19) or Grade 3 4 neutropenia (n=20) or Grade 3-4 anaemia (n=6), 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 36 days (16, 694); neutropenia 30 days (5, 110); and anaemia 36 days (8, 64).

For patients who received lisocabtagene maraleucel for MCL, Grade 3 or higher cytopenias present at Day 29 following lisocabtagene maraleucel administration, occurred in 40% of patients, and included thrombocytopenia (32%), neutropenia (24%) and anaemia (5%).

Of the 88 total patients treated in the TRANSCEND-MCL Cohort who had Day 29 laboratory findings of Grade 3-4 thrombocytopenia (n=28) or Grade 3-4 neutropenia (n=21) or Grade 3-4 anaemia (n=4), 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 (5, 302); neutropenia 30 days (8, 275); and anaemia 18 days (9, 32).

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. For patients who received lisocabtagene maraleucel for FL, adverse events of hypogammaglobulinaemia occurred in 2% of patients. For patients who received lisocabtagene maraleucel for MCL, adverse events of hypogammaglobulinaemia occurred in 7% 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% (1/172) of patients, and treatment-induced ATAs were detected in 19% (32/172) 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. In patients who received lisocabtagene maraleucel for FL (TRANSCEND-FL), pre-existing anti-therapeutic antibodies (ATAs) were detected in 1.6% (2/124) of patients, and treatment-induced or treatment-boosted ATAs were detected in 26.8% (33/123) of patients. In patients who received lisocabtagene maraleucel for MCL (TRANSCEND-MCL Cohort), pre-existing ATAs were detected in 13% (11/88) of patients, and treatment-induced or treatment-boosted ATAs were detected in 20% (17/86) of patients. The relationships between ATA status and efficacy, safety or pharmacokinetics were not conclusive due to the limited number of patients with ATAs at the study level.