Axicabtagene ciloleucel

The safety of immunisation with live viral vaccines during or following treatment with axicabtagene ciloleucel 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 axicabtagene ciloleucel treatment, and until immune recovery following treatment.

Prophylactic use of systemic corticosteroids may interfere with the activity of axicabtagene ciloleucel. 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 active central nervous system (CNS) disorder or inadequate renal, hepatic, pulmonary, or cardiac function are likely to be more vulnerable to the consequences of the adverse reactions and require special attention.

Severe neurologic adverse reactions, also known as immune effector cell-associated neurotoxicity syndrome (ICANS), have been very commonly observed in patients treated with axicabtagene ciloleucel, which could be life-threatening or fatal. Patients with a history of CNS disorders such as seizures or cerebrovascular ischaemia may be at increased risk.

There is limited clinical experience in patients with active HIV, HBV or HCV infection.

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

It is not known if axicabtagene ciloleucel 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, axicabtagene ciloleucel is not recommended for women who are pregnant, or for women of childbearing potential not using contraception. Pregnant women must be advised on the potential risks to the foetus. Pregnancy after axicabtagene ciloleucel therapy must be discussed with the treating physician.

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

It is unknown whether axicabtagene ciloleucel is 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 of the potential risk to the breast-fed child. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from axicabtagene ciloleucel therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Women of childbearing potential/Contraception in males and females

The pregnancy status of women of child bearing potential must be verified before starting axicabtagene ciloleucel 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 axicabtagene ciloleucel.

Fertility

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

Αxicabtagene ciloleucel 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 refrain from driving or operating heavy or potentially dangerous machines until at least 8 weeks after infusion or until resolution of neurologic adverse reactions.

Summary of the safety profile

The safety data described in this section are from a total of 397 adult patients treated with axicabtagene ciloleucel in three multi-centre pivotal clinical studies (ZUMA-1, ZUMA-5 and ZUMA-7) and post-marketing experience. Adverse reactions are adverse events from pivotal clinical studies and post-marketing experience medically assessed as reasonably attributed to axicabtagene ciloleucel.

Relapsed or refractory DLBCL, PMBCL and DLBCL arising from follicular lymphoma after two or more lines of systemic therapy

Safety data from ZUMA-1 reflects exposure to axicabtagene ciloleucel in a Phase ½ study in which 108 patients received CAR-positive T cells based on a recommended dose which was weight-based. The data described are from the 54-month follow-up analysis where the median actual duration of follow-up was 23.5 months (range: 0.3 to 68.2 months).

The most significant and frequently occurring adverse reactions were CRS (93%), encephalopathy (60%), and infections (40%).

Serious adverse reactions occurred in 51% of patients. The most common (≥5%) serious adverse reactions included encephalopathy (22%), unspecified pathogen infections (15%), bacterial infection (6%), viral infection (6%), febrile neutropenia (5%), and fever (5%).

The most common (≥5%) Grade 3 or higher non-haematological adverse reactions included encephalopathy (31%), unspecified pathogen infections (19%), CRS (11%), bacterial infection (9%), delirium (6%), hypertension (6%), hypotension (6%), transaminases increased (6%), and viral infection (6%). The most common Grade 3 or higher haematological adverse reactions included lymphopenia (99%), leukopenia (96%), neutropenia (94%), anaemia (65%), and thrombocytopenia (56%).

DLBCL and HGBL that relapses within 12 months from completion of, or is refractory to, first-line chemoimmunotherapy

Safety data from ZUMA-7 reflects exposure to axicabtagene ciloleucel in a Phase 3 study in which 170 patients received CAR-positive T cells based on a recommended dose which was weight-based. The data described are from an analysis where the median actual duration of follow-up was 23.2 months (range: 1.5 to 41.3 months).

The most significant and frequently occurring adverse reactions were CRS (92%), encephalopathy (49%), and infections (45%).

Serious adverse reactions occurred in 54% of patients. The most common (≥5%) serious adverse reactions included CRS (17%), encephalopathy (16%), unspecified pathogen infections (8%), fever (6%) and viral infection (5%).

The most common (≥5%) Grade 3 or higher non-haematological adverse reactions included encephalopathy (19%), unspecified pathogen infections (8%), CRS (6%), and bacterial infection (5%). The most common Grade 3 or higher haematological adverse reactions included lymphopenia (99%), leukopenia (95%), neutropenia (94%), anaemia (41%), and thrombocytopenia (26%).

Follicular lymphoma after three or more lines of systemic therapy

Safety data from ZUMA-5 reflects exposure to axicabtagene ciloleucel in a Phase 2 study in which 119 patients with relapsed/refractory FL, received CAR-positive T cells based on a recommended dose which was weight-based. The data described are from the 24-month follow-up analysis where the median actual duration of follow-up was 25.9 months (range: 0.3 to 44.3 months).

The most significant and frequently occurring adverse reactions were CRS (77%), infections (59%), and encephalopathy (47%).

Serious adverse reactions occurred in 45% of patients. The most common (≥ 5%) serious adverse reactions included encephalopathy (16%), unspecified pathogen infections (12%), CRS (12%), and bacterial infection (5%).

The most common (≥5%) Grade 3 or higher non-haematological adverse reactions included encephalopathy (14%), unspecified pathogen infections (11%), CRS (6%), and bacterial infection (5%). The most common Grade 3 or higher haematological adverse reactions included lymphopenia (99%), leukopenia (94%), neutropenia (92%), thrombocytopenia (34%), and anaemia (33%).

Tabulated list of adverse reactions

Adverse reactions described in this section were identified in patients exposed to axicabtagene ciloleucel in ZUMA-1 (n=108), ZUMA-5 (n=119), and ZUMA-7 (n=170) and from post-marketing reports. 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); uncommon (≥1/1 000 to <1/100). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Adverse drug reactions identified with axicabtagene ciloleucel:

^* Haemophagocytic lymphohistiocytosis has been reported in the setting of CRS
^** Hyperuricemia was identified from a pooled analysis of 227 adult patients treated with axicabtagene ciloleucel in ZUMA-1 and ZUMA-5
^*** Dysphagia has been reported in the setting of neurologic toxicity and encephalopathy
^# Frequency based on Grade 3 or higher laboratory parameter
^a Coagulopathy includes coagulopathy, blood fibrinogen decreased, blood fibrinogen increased, disseminated intravascular coagulation, hypofibrinogenaemia, international normalized ratio increased, prothrombin level decreased, prothrombin time prolonged
^b Immunoglobulins decreased includes blood immunoglobulin G decreased, hypogammaglobulinaemia
^c Decreased appetite includes decreased appetite, hypophagia
^d Dehydration includes dehydration, hypovolaemia
^e Delirium includes delirium, agitation, delusion, disorientation, hallucination, restlessness
^f Affective disorder includes impulsive behavior, mood altered, depression, panic attack
^g Encephalopathy includes encephalopathy, agraphia, altered state of consciousness, amnesia, aphasia, aphonia, apraxia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, dysarthria, dysgraphia, dyskinesia, dyspraxia, hypersomnia, immune effector cell-associated neurotoxicity syndrome (ICANS), lethargy, leukoencephalopathy, loss of consciousness, memory impairment, mental impairment, mental status changes, metabolic encephalopathy, neurotoxicity, slow speech, somnolence, speech disorder, stupor, toxic encephalopathy
^h Tremor includes tremor, head titubation
ⁱ Headache includes headache, head discomfort, tension headache
^j Dizziness includes dizziness, dizziness postural, presyncope, syncope, vertigo
^k Ataxia includes ataxia, balance disorder, gait disturbance
^l Facial paralysis includes facial paralysis, facial paresis
^m Neuropathy peripheral includes neuropathy peripheral, allodynia, cervical radiculopathy, hyperaesthesia, hypoaesthesia, lumbar radiculopathy, paraesthesia, peripheral sensory neuropathy, peroneal nerve palsy
ⁿ Visual impairment includes visual impairment, hemianopia, vision blurred, visual acuity reduced
° Tachycardia includes tachycardia, postural orthostatic tachycardia syndrome, sinus tachycardia
^p Arrhythmia includes arrhythmia, atrial fibrillation, atrial flutter, atrioventricular block, bradycardia, bundle branch block right, electrocardiogram QT prolonged, extrasystoles, heart rate increased, heart rate irregular, sinus bradycardia, supraventricular extrasystoles, supraventricular tachycardia, ventricular arrhythmia, ventricular extrasystoles, ventricular tachycardia
^q Cardiac failure includes cardiac failure, acute left ventricular failure, ejection fraction decreased, stress cardiomyopathy
^r Hypotension includes hypotension, capillary leak syndrome, diastolic hypotension, hypoperfusion, orthostatic hypotension
^s Thrombosis includes thrombosis, axillary vein thrombosis, brachiocephalic vein thrombosis, deep vein thrombosis, device occlusion, embolism, jugular vein thrombosis, peripheral embolism, peripheral ischaemia, pulmonary embolism, splenic vein thrombosis, thrombosis in device
^t Cough includes cough, productive cough, upper-airway cough syndrome
^u Respiratory failure includes respiratory failure, acute respiratory failure
^v Hypoxia includes hypoxia, oxygen saturation decreased
^w Dyspnoea includes dyspnoea, dyspnoea exertional
^x Nasal inflammation includes rhinitis allergic, rhinorrhoea
^y Diarrhoea includes diarrhoea, colitis, enteritis
^z Abdominal pain includes abdominal pain, abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, dyspepsia, epigastric discomfort
^aa Dry mouth includes dry mouth, lip dry
^bb Transaminases increased includes transaminases increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hypertransaminasaemia
^cc Hyperbilirubinaemia increased includes hyperbilirubinemia, blood bilirubin increased
^dd Rash includes rash, application site rash, dermatitis, dermatitis allergic, dermatitis bullous, erythema, pruritus, rash erythematous, rash macular, rash maculo-papular, rash pruritic, rash pustular, urticaria
^ee Motor dysfunction includes motor dysfunction, muscle contractions involuntary, muscle rigidity, muscle spasms, muscle spasticity, muscle strain, muscle tightness, muscle twitching, muscular weakness
^ff Musculoskeletal pain includes musculoskeletal pain, arthralgia, arthritis, back pain, bone pain, flank pain, groin pain, musculoskeletal chest pain, myalgia, neck pain, osteoarthritis, pain in extremity
^gg Renal impairment includes acute kidney injury, blood creatinine increased, renal failure
^hh. Fever includes hyperthermia, pyrexia
ⁱⁱ Oedema includes oedema, face oedema, generalized oedema, localized oedema, oedema genital, oedema peripheral, peripheral swelling, swelling
^jj Fatigue includes fatigue, asthenia, decreased activity, malaise

Description of selected adverse reactions

Cytokine release syndrome

In ZUMA-1 and ZUMA-7, CRS occurred in 92% of patients. Eight percent (8%) of patients experienced Grade 3 or higher (severe, life-threatening, and fatal) CRS. The median time to onset was 3 days (range: 1 to 12 days) and the median duration was 7 days (range: 2 to 58 days). Ninety-nine percent (99%) of patients recovered from CRS. No CRS was reported by patients treated with standard of care therapy (SOCT) in ZUMA-7.

In ZUMA-5, CRS occurred in 77% of patients. Six percent (6%) of patients experienced Grade 3 or higher (severe, life-threatening, and fatal) CRS. The median time to onset was 4 days (range: 1 to 11 days) and the median duration was 6 days (range: 1 to 27 days). Ninety-nine percent (99%) of patients recovered from CRS.

The most common adverse reactions (≥20%) that may be associated with CRS included pyrexia (89%), hypotension (50%), tachycardia (47%), chills (30%), and hypoxia (24%). Serious adverse reactions that may be associated with CRS included pyrexia (12%), hypotension (5%), hypoxia (3%), arrhythmia (3%), cardiac failure (2%), fatigue (2%), headache (2%), tachycardia (2%), cardiac arrest (1%), dyspnoea (1%), and tachypnoea (1%).

Neurologic adverse reactions

In ZUMA-1 and ZUMA-7, neurologic adverse reactions occurred in 63% of patients. Twenty-five percent (25%) of patients experienced Grade 3 or higher (severe or life-threatening) adverse reactions. Neurologic toxicities occurred within the first 7 days of infusion for 75% of patients. The median time to onset was 6 days (range: 1 to 133 days). The median duration was 10 days, with resolution occurring within 3 weeks for 66% of patients following infusion.

In ZUMA-5, neurologic adverse reactions occurred in 57% of patients. Sixteen percent (16%) of patients experienced Grade 3 or higher (severe or life-threatening) adverse reactions. Neurologic toxicities occurred within the first 7 days of infusion for 65% of patients. The median time to onset was 7 days (range: 1 to 177 days). The median duration was 14 days, with resolution occurring within 3 weeks for 60% of patients following infusion.

The most common (≥5%) neurologic adverse reactions included encephalopathy (51%), tremor (28%), and delirium (14%). Serious neurologic adverse reactions reported in patients included encephalopathy (18%), tremor (2%), delirium (2%), hemiparesis (1%) and seizure (1%). In ZUMA-7, encephalopathy and tremor were reported in 49% and 25% of patients treated with axicabtagene ciloleucel compared to 8% and 1% treated with SOCT, respectively.

Other neurologic adverse reactions have been reported less frequently in clinical trials and included dysphagia (3%), myelitis (0.2%), and quadriplegia (0.1%).

Febrile neutropenia and infections

Febrile neutropenia was observed in 10% of patients after axicabtagene ciloleucel infusion. Infections occurred in 48% of patients. Grade 3 or higher (severe, life-threatening, or fatal) infections occurred in 19% of patients. Grade 3 or higher unspecified pathogen, bacterial, and viral infections occurred in 12%, 6%, and 5% of patients respectively. The most common site of unspecified pathogen infection was in the respiratory tract. In ZUMA-7, febrile neutropenia and viral infection were reported in 2% and 16% of patients treated with axicabtagene ciloleucel compared to 27% and 5% treated with SOCT, respectively.

Prolonged cytopenias

Grade 3 or higher neutropenia (including febrile neutropenia), anaemia, and thrombocytopenia occurred in 68%, 31%, and 23% of patients, respectively. Prolonged (still present at Day 30 or with an onset at Day 30 or beyond) Grade 3 or higher neutropenia, thrombocytopenia, and anaemia occurred in 26%, 12%, and 6% of patients, respectively. In ZUMA-1, at the time of the 24-month follow-up analysis, Grade 3 or higher neutropenia, thrombocytopenia, and anaemia present after Day 93 occurred in 11%, 7%, and 3% of patients, respectively. In ZUMA-7, Grade 3 or higher neutropenia and thrombocytopenia were reported in 94% and 26% of patients treated with axicabtagene ciloleucel compared to 51% and 63% treated with SOCT, respectively.

Hypogammaglobulinaemia

Hypogammaglobulinaemia was reported in 15% of patients treated with axicabtagene ciloleucel. Cumulatively, 36 (33%) of 108 patients in ZUMA-1 received intravenous immunoglobulin therapy by the time of the 54-month analysis, 28 (16%) of 170 patients in ZUMA-7 received intravenous immunoglobulin therapy by the time of the 23.2 month analysis and 33 (28%) of 119 subjects in ZUMA-5 received intravenous immunoglobulin therapy at the time of the 24-month follow-up analysis. In ZUMA-7, immunoglobulins decreased was reported in 11% of patients treated with axicabtagene ciloleucel compared to 1% of patients treated with SOCT.

Immunogenicity

The immunogenicity of axicabtagene ciloleucel 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. Eleven out of 278 patients (4%) tested positive for anti-FMC63 antibodies prior to being treated with axicabtagene ciloleucel in ZUMA-1 and ZUMA-7, and 1 patient (1%) in ZUMA-7 who had a negative test result prior to treatment, had a positive test result after treatment in the screening ELISA. Results of a confirmatory cell-based assay, leveraging a properly folded and expressed extracellular portion of the CAR (ScFv, hinge and linker) demonstrated that all patients treated with axicabtagene ciloleucel that had a positive result in the screening ELISA were antibody negative at all time points tested. There is no evidence that the kinetics of initial expansion and persistence of axicabtagene ciloleucel, or the safety or effectiveness of axicabtagene ciloleucel, was altered in these patients. In ZUMA-5, 13 out of 116 patients (11%) tested positive for antibodies in the ELISA screening assay prior to being treated with axicabtagene ciloleucel, and 2 subjects who had negative results prior to treatment had positive test results after treatment. Results of a confirmatory cell-based assay demonstrated that all patients treated with axicabtagene ciloleucel that had an ELISA positive result were antibody negative, before, during and after treatment.

Special population

There is limited experience with axicabtagene ciloleucel in patients ≥75 years of age. Generally, safety and efficacy were similar between patients ≥65 years and patients <65 years of age treated with axicabtagene ciloleucel. Outcomes were consistent between patients with Eastern Cooperative Oncology Group (ECOG) of 0 and 1 and by sex.