BREXUCABTAGENE AUTOLEUCEL: 1,747 Adverse Event Reports & Safety Profile

TECARTUS (brexucabtagene autoleucel) is a CD19-directed genetically modified autologous T cell immunotherapy. To prepare TECARTUS, a patient's own T cells are harvested and genetically modified ex vivo by retroviral transduction to express a chimeric antigen receptor (CAR) comprising a murine anti-CD19 single-chain variable fragment (scFv) linked to CD28 and CD3-zeta co-stimulatory domains. The anti-CD19 CAR T cells are expanded and infused back into the patient, where they can recognize and eliminate CD19-expressing target cells. TECARTUS is prepared from the patient's peripheral blood mononuclear cells, which are obtained via a standard leukapheresis procedure. The mononuclear cells are enriched for T cells and activated with anti-CD3 and anti-CD28 antibodies in the presence of IL-2, then transduced with a replication-incompetent retroviral vector containing the anti-CD19 CAR transgene. The transduced T cells are expanded in cell culture, washed, formulated into a suspension, and cryopreserved. The manufacture of TECARTUS includes a T cell enrichment step that may reduce the likelihood of circulating CD19-expressing tumor cells in patients' leukapheresis material driving the activation, expansion, and exhaustion of the anti-CD19 CAR T cells during the ex vivo manufacturing process. The product must pass a sterility test before release for shipping as a frozen suspension in a patient-specific infusion bag. The product is thawed prior to infusion [see Dosage and Administration (2.2) , How Supplied/Storage and Handling (16) ] . In addition to T cells, TECARTUS may contain natural killer (NK) cells. The formulation contains CryoStor (dimethyl sulfoxide [DMSO], final concentration, 5%), sodium chloride (NaCl), and Human Serum Albumin (HSA).

AND USAGE TECARTUS is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of: TECARTUS is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of: Adult patients with relapsed or refractory mantle cell lymphoma (MCL). This indication is approved under accelerated approval based on overall response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

1.1 Mantle Cell Lymphoma Adult patients with relapsed or refractory mantle cell lymphoma (MCL). This indication is approved under accelerated approval based on overall response rate and durability of response <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

1.2 Acute Lymphoblastic Leukemia Adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

AND ADMINISTRATION For autologous use only. For intravenous use only. Each single infusion bag of TECARTUS contains a suspension of chimeric antigen receptor (CAR)-positive T cells in approximately 68 mL. For autologous use only. For intravenous use only. Do NOT use a leukodepleting filter. Administer a lymphodepleting regimen of cyclophosphamide and fludarabine before infusion of TECARTUS. ( 2.2 ) Verify the patient's identity prior to infusion. ( 2.2 ) Premedicate with acetaminophen and diphenhydramine. ( 2.2 ) Confirm availability of tocilizumab prior to infusion. ( 2.2 , 5.1 ) Dosing of TECARTUS is based on the number of chimeric antigen receptor (CAR)-positive viable T cells. ( 2.1 ) MCL: dose is 2 × 10 6 CAR-positive viable T cells per kg body weight, with a maximum of 2 × 10 8 CAR-positive viable T cells. ( 2.1 ) ALL: dose is 1 × 10 6 CAR-positive viable T cells per kg body weight, with a maximum of 1 × 10 8 CAR-positive viable T cells. ( 2.1 )

2.1 Dose Recommended Dosage for MCL The target dose is 2 × 10 6 CAR-positive viable T cells per kg body weight, with a maximum of 2 × 10 8 CAR-positive viable T cells.

Recommended

Dosage for ALL The target dose is 1 × 10 6 CAR-positive viable T cells per kg body weight, with a maximum of 1 × 10 8 CAR-positive viable T cells.

2.2 Administration TECARTUS is for autologous use only. The patient&apos;s identity must match the patient identifiers on the TECARTUS cassette and infusion bag. Do not infuse TECARTUS if the information on the patient-specific label does not match the intended patient.

Preparing

Patient for TECARTUS Infusion Confirm availability of TECARTUS prior to starting the lymphodepleting chemotherapy regimen. Pre-treatment MCL: Administer a lymphodepleting chemotherapy regimen of cyclophosphamide 500 mg/m 2 intravenously and fludarabine 30 mg/m 2 intravenously on each of the fifth, fourth, and third day before infusion of TECARTUS. ALL: Administer a lymphodepleting chemotherapy regimen of fludarabine 25 mg/m 2 intravenously over 30 minutes on the fourth, third, and second day and administer cyclophosphamide 900 mg/m 2 over 60 minutes on the second day before infusion of TECARTUS.

Premedication

Premedicate with acetaminophen and diphenhydramine or another H1-antihistamine approximately 30 to 60 minutes prior to TECARTUS infusion. Avoid prophylactic use of systemic corticosteroids as it may interfere with the activity of TECARTUS. Preparation of TECARTUS for infusion Coordinate the timing of TECARTUS thaw and infusion. Confirm the infusion time in advance, and adjust the start time of TECARTUS thaw such that TECARTUS will be available for infusion when the patient is ready. Confirm patient identity: Prior to TECARTUS preparation, match the patient's identity with the patient identifiers on the TECARTUS cassette. Do not remove the TECARTUS infusion bag from the cassette if the patient information on the cassette label does not match the intended patient. Once patient identity is confirmed, remove the TECARTUS infusion bag from the cassette and check that the patient information on the cassette label matches the patient information on the bag label. Inspect the infusion bag for any breaches of container integrity such as breaks or cracks before thawing. If the bag is compromised, follow the local guidelines (or call Kite at 1-844-454-KITE). Place the infusion bag inside a second sterile bag per local guidelines. Thaw the infusion bag at approximately 37°C using either a water bath or dry-thaw method until there is no visible ice in the infusion bag. Gently mix the contents of the bag to disperse clumps of cellular material. If visible cell clumps remain, continue to gently mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing. Do not wash, spin down, and/or re-suspend TECARTUS in new media prior to infusion. Once thawed, TECARTUS should be administered within 30 minutes but may be stored at room temperature (20°C to 25°C) for up to three hours.

Administration

For autologous use only. Confirm that tocilizumab and emergency equipment are available prior to infusion and during the recovery period. Do NOT use a leukodepleting filter. Central venous access is recommended for the administration of TECARTUS. Confirm that the patient's identity matches the patient identifiers on the TECARTUS infusion bag. Prime the tubing with normal saline prior to infusion. Infuse the entire contents of the TECARTUS bag within 30 minutes by either gravity or a peristaltic pump. TECARTUS is stable at room temperature for up to three hours after thaw. Gently agitate the TECARTUS bag during infusion to prevent cell clumping. After the entire contents of the TECARTUS bag are infused, rinse the tubing with normal saline at the same infusion rate to ensure all product is delivered. TECARTUS contains human blood cells that are genetically modified with replication-incompetent retroviral vector. Follow universal precautions and local biosafety guidelines for handling and disposal of TECARTUS to avoid potential transmission of infectious diseases.

Monitoring

Monitor patients daily for at least 7 days following infusion for signs and symptoms of Cytokine Release Syndrome (CRS) and neurologic events. Instruct patients to remain within proximity of a healthcare facility for at least 2 weeks following infusion. Advise patients to avoid driving for at least 2 weeks following infusion.

2.3 Management of Severe Adverse Reactions Cytokine Release Syndrome (CRS) Identify CRS based on clinical presentation <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> . Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to the recommendations in Table 1. Patients who experience Grade 2 or higher CRS (e.g., hypotension, not responsive to fluids, or hypoxia requiring supplemental oxygenation) should be monitored with continuous cardiac telemetry and pulse oximetry. For patients experiencing severe CRS, consider performing an echocardiogram to assess cardiac function. For severe or life-threatening CRS, consider intensive care supportive therapy. Physicians may also consider management per current practice guidelines.

Table

1.

Crs

Grading and Management Guidance CRS Grade Lee et al. 2014.

Tocilizumab Corticosteroids Grade

1 Symptoms require symptomatic treatment only (e.g., fever, nausea, fatigue, headache, myalgia, malaise). If not improving after 24 hours, administer tocilizumab Refer to tocilizumab Prescribing Information for details. 8 mg/kg intravenously over 1 hour (not to exceed 800 mg). Not applicable.

Grade

2 Symptoms require and respond to moderate intervention. Oxygen requirement less than 40% FiO 2 or hypotension responsive to fluids or low dose of one vasopressor or Grade 2 organ toxicity. Refer to Table 2 for management of neurologic toxicity. Administer tocilizumab 8 mg/kg intravenously over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids or increasing supplemental oxygen. Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses if no clinical improvement in the signs and symptoms of CRS. If improving, discontinue tocilizumab. Manage per Grade 3 if no improvement within 24 hours after starting tocilizumab. If improving, taper corticosteroids.

Grade

3 Symptoms require and respond to aggressive intervention. Oxygen requirement greater than or equal to 40% FiO 2 or hypotension requiring high-dose or multiple vasopressors or Grade 3 organ toxicity or Grade 4 transaminitis.

Per Grade

2 If improving, discontinue tocilizumab. Administer methylprednisolone 1 mg/kg intravenously twice daily or equivalent dexamethasone (e.g., 10 mg intravenously every 6 hours) until Grade 1, then taper corticosteroids. If improving, manage as Grade 2. If not improving, manage as Grade 4.

Grade

4 Life-threatening symptoms. Requirements for ventilator support or continuous veno-venous hemodialysis (CVVHD), or Grade 4 organ toxicity (excluding transaminitis).

Per Grade

2 If improving, discontinue tocilizumab. Administer methylprednisolone 1000 mg intravenously per day for 3 days. If improving, taper corticosteroids, and manage as Grade 3. If not improving, consider alternate immunosuppressants.

Neurologic Toxicity

Monitor patients for signs and symptoms of neurologic toxicities/immune effector cell-associated neurotoxicity syndrome (ICANS) (Table 2). Rule out other causes of neurologic symptoms. Patients who experience Grade 2 or higher neurologic toxicities/ICANS should be monitored with continuous cardiac telemetry and pulse oximetry. Provide intensive care supportive therapy for severe or life-threatening neurologic toxicities. Consider non-sedating anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis for any Grade 2 or higher neurologic toxicities. Physicians may also consider management per current practice guidelines.

Table

2.

Neurologic

Toxicity/ICANS Grading and Management Guidance Neurologic Event Severity based on Common Terminology Criteria for Adverse Events. Concurrent CRS No Concurrent CRS Abbreviation: ADLs, activities of daily living.

Grade

1 Examples include: Somnolence – mild drowsiness or sleepiness Confusion – mild disorientation Encephalopathy – mild limiting of ADLs Dysphasia – not impairing ability to communicate Administer tocilizumab per Table 1 for management of Grade 1 CRS. Supportive care.

Grade

2 Examples include: Somnolence – moderate limiting instrumental ADLs Confusion – moderate disorientation Encephalopathy – limiting instrumental ADLs Dysphasia moderate impairing ability to communicate spontaneously Seizure(s) Administer tocilizumab per Table 1 for management of Grade 2 CRS. If not improving within 24 hours after starting tocilizumab, administer dexamethasone 10 mg intravenously every 6 hours until the event is Grade 1 or less, then taper corticosteroids. If improving, discontinue tocilizumab. If still not improving, manage as Grade 3. Administer dexamethasone 10 mg intravenously every 6 hours until the event is Grade 1 or less. If improving, taper corticosteroids. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.

Grade

3 Examples include: Somnolence – obtundation or stupor Confusion – severe disorientation Encephalopathy – limiting self-care ADLs Dysphasia – severe receptive or expressive characteristics, impairing ability to read, write, or communicate intelligibly Administer tocilizumab per Table 1 for management of Grade 2 CRS. In addition, administer dexamethasone 10 mg intravenously with the first dose of tocilizumab and repeat dose every 6 hours. Continue dexamethasone use until the event is Grade 1 or less, then taper corticosteroids. If improving, discontinue tocilizumab and manage as Grade 2. If still not improving, manage as Grade 4. Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until the event is Grade 1 or less, then taper corticosteroids. If not improving, manage as Grade 4. Consider non-sedating anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.

Grade

4 Life-threatening consequences Urgent intervention indicated Requirement for mechanical ventilation Consider cerebral edema Administer tocilizumab per Table 1 for management of Grade 2 CRS. Administer methylprednisolone 1000 mg intravenously per day with first dose of tocilizumab and continue methylprednisolone 1000 mg intravenously per day for 2 more days. If improving, then manage as Grade 3. If not improving, consider alternate immunosuppressants. Administer methylprednisolone 1000 mg intravenously per day for 3 days. If improving, then manage as Grade 3. If not improving, consider alternate immunosuppressants. Consider non-sedating anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.

None. None. ( 4 )

REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Cytokine Release Syndrome [see Warnings and Precautions (5.1) ]

Neurologic

Toxicities [see Warnings and Precautions (5.2) ]

Hemophagocytic Lymphohistiocytosis/Macrophage

Activation Syndrome [see Warnings and Precautions (5.3) ]

Hypersensitivity

Reactions [see Warnings and Precautions (5.4) ]

Severe

Infections [see Warnings and Precautions (5.5) ]

Prolonged

Cytopenias [see Warnings and Precautions (5.6) ] Hypogammaglobulinemia [see Warnings and Precautions (5.7) ] The most common non-laboratory adverse reactions (incidence greater than or equal to 20%) are: MCL: fever, CRS, hypotension, encephalopathy, fatigue, tachycardia, arrhythmia, infection with pathogen unspecified, chills, hypoxia, cough, tremor, musculoskeletal pain, headache, nausea, edema, motor dysfunction, constipation, diarrhea, decreased appetite, dyspnea, rash, insomnia, pleural effusion, and aphasia. ( 6.1 ) ALL: fever, CRS, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting. ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Kite at 1-844-454-KITE (5483) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Patients with Relapsed/Refractory Mantle Cell Lymphoma (MCL) The safety of TECARTUS was evaluated in a Phase 2 single-arm clinical study (ZUMA-2) in which a total of 82 patients with relapsed/refractory MCL received a single dose of CAR-positive viable T cells (2 × 10 6 or 0.5 × 10 6 anti-CD19 CAR T cells/kg) that was weight-based <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span> . The most common adverse reactions (incidence ≥ 20%) were fever, CRS, hypotension, encephalopathy, fatigue, tachycardia, arrhythmia, infection with pathogen unspecified, chills, hypoxia, cough, tremor, musculoskeletal pain, headache, nausea, edema, motor dysfunction, constipation, diarrhea, decreased appetite, dyspnea, rash, insomnia, pleural effusion, and aphasia. Serious adverse reactions occurred in 66% of patients. The most common serious adverse reactions (&gt; 2%) were encephalopathy, fever, infection with pathogen unspecified, CRS, hypoxia, aphasia, renal insufficiency, pleural effusion, respiratory failure, bacterial infections, dyspnea, fatigue, arrhythmia, tachycardia, and viral infections. The most common (≥ 10%)

Grade

3 or higher reactions were anemia, neutropenia, thrombocytopenia, hypotension, hypophosphatemia, encephalopathy, leukopenia, hypoxia, fever, hyponatremia, hypertension, infection with pathogen unspecified, pneumonia, hypocalcemia, and lymphopenia.

Table

3 summarizes the adverse reactions that occurred in at least 10% of patients treated with TECARTUS and Table 4 describes the laboratory abnormalities of Grade 3 or 4 that occurred in at least 10% of patients.

Table

3. Summary of Adverse Reactions Observed in at Least 10% of Patients Treated with TECARTUS in ZUMA-2 (N=82)

Adverse Reaction Any

Grade (%)

Grade

3 or Higher (%) Blood and Lymphatic System Disorders Coagulopathy Coagulopathy includes coagulopathy, disseminated intravascular coagulation, international normalized ratio increased. 10 2 Cardiac Disorders Tachycardias Tachycardias includes tachycardia, sinus tachycardia. 45 0 Bradycardias Bradycardias includes bradycardia, sinus bradycardia. 10 0 Non-ventricular Arrhythmias Non-ventricular arrhythmias includes atrial fibrillation, atrial flutter, cardiac flutter, palpitations, supraventricular tachycardia. 10 4 Gastrointestinal Disorders Nausea 35 1 Constipation 29 0 Diarrhea 28 5 Abdominal pain Abdominal pain includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness. 17 0 Oral pain Oral pain includes oral pain, gingival pain, lip pain, oral mucosal erythema, oropharyngeal pain. 16 0 Vomiting Vomiting includes vomiting, retching. 13 0 Dysphagia 10 2 General Disorders and Administration Site Conditions Fever 94 15 Fatigue Fatigue includes fatigue, lethargy, malaise. 48 1 Chills 41 0 Edema Edema includes eyelid edema, face edema, generalized edema, localised edema, edema, edema peripheral, periorbital edema, peripheral swelling, scrotal edema, swelling face. 35 2 Pain Pain includes pain, allodynia, dysaesthesia, ear pain, facial pain, non-cardiac chest pain. 17 2 Immune System Disorders Cytokine release syndrome 91 18 Hypogammaglobulinemia Hypogammaglobulinemia includes hypogammaglobulinemia, blood immunoglobulin G decreased. 16 1 Infections and Infestations Infection with pathogen unspecified 43 24 Viral infections 18 4 Bacterial infections 13 6 Metabolism and Nutrition Disorders Decreased appetite 26 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Musculoskeletal pain includes musculoskeletal pain, arthralgia, back pain, bone pain, dysarthria, flank pain, groin pain, myalgia, neck pain, pain in extremity. 37 2 Motor dysfunction Motor dysfunction includes asthenia, intensive care acquired weakness, mobility decreased, muscle twitching, muscular weakness, myopathy. 17 4 Nervous System Disorders Encephalopathy Encephalopathy includes encephalopathy, altered state of consciousness, amnesia, balance disorder, cognitive disorder, confusional state, disturbance in attention, dysgraphia, dyskinesia, memory impairment, mental status changes, neurotoxicity, somnolence. 51 24 Tremor 38 2 Headache Headache includes headache, migraine. 35 1 Aphasia Aphasia includes aphasia, communication disorder. 20 7 Dizziness Dizziness includes dizziness, presyncope, syncope. 18 6 Neuropathy Neuropathy includes hyperaesthesia, neuropathy peripheral, paraesthesia, paraesthesia oral. 13 2 Psychiatric Disorders Insomnia 21 0 Delirium Delirium includes delirium, agitation, disorientation, hallucination, hypomania, irritability, nervousness, personality change. 18 5 Anxiety 16 0 Renal and Urinary Disorders Renal insufficiency Renal insufficiency includes acute kidney injury, blood creatinine increased. 18 9 Urine output decreased Urine output decreased includes urine output decreased, urinary retention. 11 1 Respiratory, Thoracic and Mediastinal Disorders Hypoxia 40 20 Cough Cough includes cough, upper-airway cough syndrome. 38 0 Dyspnea Dyspnea includes dyspnea, dyspnea exertional. 24 6 Pleural effusion 21 5 Skin and Subcutaneous Tissue Disorders Rash Rash includes rash, erythema, rash erythematous, rash maculo-papular, rash pustular. 22 4 Vascular Disorders Hypotension Hypotension includes hypotension, orthostatic hypotension. 57 27 Hypertension 18 11 Thrombosis Thrombosis includes thrombosis, deep vein thrombosis, embolism, pulmonary embolism. 17 4 Other clinically important adverse reactions that occurred in less than 10% of patients treated with TECARTUS include the following: Gastrointestinal disorders: dry mouth (7%) Infections and infestations disorders: fungal infections (9%) Metabolism and nutrition disorders: dehydration (6%) Nervous system disorders: ataxia (7%), seizure (5%), increased intracranial pressure (2%) Respiratory, thoracic and mediastinal disorders: respiratory failure (6%), pulmonary edema (4%) Skin and subcutaneous tissue disorders: rash (9%) Vascular disorders: hemorrhage (7%)

Table

4.

Grade

3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients in ZUMA-2 Following TECARTUS Infusion (N = 82)

Grades

3 or 4 (%)

Leukopenia

95 Neutropenia 95 Lymphopenia 86 Thrombocytopenia 63 Anemia 55 Hypophosphatemia 30 Hypocalcemia 21 Blood uric acid increased 17 Hyponatremia 16 Aspartate Aminotransferase increased 15 Alanine Aminotransferase increased 15 Hypokalemia 10 Patients with Relapsed/Refractory B-cell precursor Acute Lymphoblastic Leukemia (ALL) The safety of TECARTUS was evaluated in a Phase 1/2 open-label, multicenter study (ZUMA-3) in which a total of 78 patients with relapsed/refractory ALL received a single dose of CAR-positive T cells (1 × 10 6 anti-CD19 CAR T cells/kg) that was weight-based [see Clinical Studies (14.2) ] . The most common non-laboratory adverse reactions (≥ 20%) were fever, cytokine release syndrome, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting. The most common serious adverse reactions (≥ 2%) were cytokine release syndrome, febrile neutropenia, hypotension, encephalopathy, fever, infection with pathogen unspecified, hypoxia, tachycardia, bacterial infections, respiratory failure, seizure, diarrhea, dyspnea, fungal infections, viral infections, coagulopathy, delirium, fatigue, hemophagocytic lymphohistiocytosis, musculoskeletal pain, edema, and paraparesis. The most common (≥ 10%)

Grade

3 or 4 reactions were fever, febrile neutropenia, hypotension, encephalopathy, cytokine release syndrome, hypoxia, and infection with pathogen unspecified. Fatal adverse reactions occurred in 5% (4/78) of patients including cerebral edema, sepsis, and fungal pneumonia. Of the 4 patients who had fatal adverse reactions: one patient with fatal pneumonia had pre-existing pneumonia prior to study enrollment, and one patient with fatal sepsis had prolonged cytopenia and immunosuppression from prior therapies and underlying disease.

Table

5 summarizes the adverse reactions (excluding laboratory abnormalities) that occurred in at least 10% of patients treated with TECARTUS and Table 6 describes the laboratory abnormalities of Grade 3 or 4 that occurred in at least 10% of patients.

Table

5. Summary of Adverse Reactions Observed in at Least 10% of Patients Treated with TECARTUS in ZUMA-3 (N=78)

Adverse Reaction Any

Grade (%)

Grade

3 or Higher (%) Blood and Lymphatic System Disorders Febrile Neutropenia Febrile neutropenia includes febrile neutropenia (11 (14%)) and fever occurring concurrently with neutropenia events (16 (21%)). 35 35 Coagulopathy Coagulopathy includes blood fibrinogen decreased, coagulopathy, disseminated intravascular coagulation, hypofibrinogenemia, international normalized ratio increased. 17 5 Cardiac Disorders Tachycardias Tachycardias includes sinus tachycardia, tachycardia. 63 6 Arrhythmia Arrhythmia includes arrhythmia, arrhythmia supraventricular, atrial fibrillation, atrial flutter, atrial tachycardia, bradycardia, cardiac arrest, electrocardiogram QT prolonged, electrocardiogram T wave inversion, pulseless electrical activity, sinus bradycardia, supraventricular tachycardia, ventricular tachycardia. 15 1 Gastrointestinal Disorders Nausea 41 1 Diarrhea 32 6 Abdominal pain Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain upper. 19 0 Constipation 24 0 Vomiting 21 3 General Disorders and Administration Site Conditions Fever 96 38 Chills 40 0 Edema Edema includes face edema, fluid overload, generalized edema, edema, edema peripheral, swelling face, tongue edema. 29 5 Fatigue Fatigue includes asthenia, cancer fatigue, fatigue, malaise. 37 1 Pain 13 1 Immune System Disorders Cytokine release syndrome 92 26 Infections and Infestations Infection with pathogen unspecified Infection with pathogen unspecified includes, catheter bacteremia, conjunctivitis, device related infection, mucosal infection, nasopharyngitis, parotitis, pneumonia, sepsis, septic shock, sinusitis, upper respiratory tract infection, urinary tract infection. 28 22 Bacterial infections Bacterial infections includes bacteremia, bacterial disease carrier, cellulitis, cellulitis of male external genital organ, clostridial infection, clostridium difficile colitis, clostridium difficile infection, enterococcal bacteremia, enterococcal infection, escherichia bacteremia, escherichia infection, escherichia sepsis, pseudomonas infection, staphylococcal bacteremia, staphylococcal infection, wound infection staphylococcal. 15 8 Fungal infections Fungal infections includes bronchopulmonary aspergillosis, candida infection, fungal skin infection, mycotic oral candidiasis, osteomyelitis fungal, pneumocystis jirovecii pneumonia, pneumonia fungal, sinusitis fungal. 13 5 Metabolism and Nutrition Disorders Decreased appetite 22 1 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Musculoskeletal pain includes arthralgia, back pain, bone pain, coccydynia, muscle strain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity. 32 5 Muscular weakness 14 1 Nervous System Disorders Encephalopathy Encephalopathy includes altered state of consciousness, aphasia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, dysarthria, dysgraphia, encephalopathy, immune effector cell-associated neurotoxicity syndrome, memory impairment, mental status changes, slow response to stimuli, slow speech, somnolence, speech disorder. 63 27 Headache 38 1 Tremor 29 1 Dizziness Dizziness includes dizziness, syncope. 13 1 Psychiatric Disorders Delirium Delirium includes agitation, delirium, delusion, disorientation, hallucination. 18 5 Anxiety 12 0 Insomnia 13 0 Respiratory, Thoracic and Mediastinal Disorders Hypoxia 31 23 Cough Cough includes cough, productive cough. 12 0 Dyspnea 12 1 Skin and Subcutaneous Tissue Disorders Rash Rash includes catheter site urticaria, dermatitis bullous, drug eruption, pruritus, rash, rash macular, rash maculo-papular, rash pustular, toxic skin eruption, urticaria. 31 0 Vascular Disorders Hypotension Hypotension includes hypotension, orthostatic hypotension. 69 33 Hemorrhage Hemorrhage includes conjunctival hemorrhage, contusion, epistaxis, gastric hemorrhage, hematoma, hematoma muscle, hemorrhage intracranial, hemorrhoidal hemorrhage, menorrhagia, petechiae, pulmonary alveolar hemorrhage, retinal hemorrhage, vaginal hemorrhage, vitreous hemorrhage. 13 4 Hypertension 13 6 Other clinically important adverse reactions that occurred in less than 10% of patients treated with TECARTUS include the following: Cardiac disorder: cardiac failure (4%), palpitations (3%) Eye disorders: visual impairment (9%) Gastrointestinal disorders: dry mouth (6%), dysphagia (4%), oral pain (1%) Immune system disorders: hypogammaglobulinemia (9%), hemophagocytic lymphohistiocytosis (4%), drug hypersensitivity (1%) Infections and infestations: viral infections (6%) Metabolism and nutrition disorders: dehydration (5%), tumor lysis syndrome (1%) Musculoskeletal and connective tissue disorders: muscle spasms (4%), musculoskeletal stiffness (3%) Nervous system disorders: seizure (8%), ataxia (5%), peripheral neuropathy (4%), myoclonus (3%), paraparesis (3%), brain edema (1%), brain herniation (1%), cauda equina syndrome (1%), monoplegia (1%) Renal and urinary disorders: renal impairment (6%) Respiratory, thoracic and mediastinal disorders: respiratory failure (9%), pulmonary edema (6%), pleural effusion (4%), pneumonitis (4%) Skin and subcutaneous tissue disorders: skin lesion (4%), decubitus ulcer (3%), dry skin (3%), skin ulcer (3%), alopecia (1%), hyperhidrosis (1%), skin hyperpigmentation (1%) Vascular disorders: thrombosis (4%)

Table

6.

Grade

3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients in ZUMA-3 Following TECARTUS Infusion (N = 78)

Grades

3 or 4 (%)

Leukopenia

99 Neutropenia 97 Lymphopenia 96 Thrombocytopenia 87 Anemia 77 Hypophosphatemia 47 Alanine aminotransferase increased 31 Aspartate aminotransferase increased 23 Hyperglycemia 22 Hypocalcemia 22 Blood uric acid increased 19 Direct bilirubin increased 19 Hyponatremia 19 Hypokalemia 13 Hyperbilirubinemia 10

6.2 Immunogenicity TECARTUS has the potential to induce anti-product antibodies, which 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-CAR T cell antibody immunogenicity has been observed in ZUMA-2. Based on an initial screening assay in ZUMA-2, 17 of 82 patients tested positive for antibodies at any timepoint; however, a confirmatory orthogonal cell-based assay demonstrated that all 17 patients were antibody negative at all timepoints tested. Based on an initial screening assay in ZUMA-3, 16 of 100 patients 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 antibody result at retreatment Day 28 and Month 3. There is no evidence that the kinetics of initial expansion and persistence of TECARTUS, or the safety or effectiveness of TECARTUS, were altered in these patients.

6.3 Postmarketing Experience Because adverse events to marketed products are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. The following adverse event has been identified during postmarketing use of TECARTUS.

Immune System

Disorders : Infusion related reaction The following adverse event has been identified during postmarketing use of BCMA- or CD19-directed genetically modified autologous T cell immunotherapies: Neoplasms : T cell malignancies

AND PRECAUTIONS Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome: Administer treatment per institutional standards. ( 5.3 )

Hypersensitivity

Reactions: Monitor for hypersensitivity reactions during infusion. ( 5.4 )

Severe

Infections: Monitor patients for signs and symptoms of infection; treat appropriately. ( 5.5 )

Prolonged

Cytopenias: Patients may exhibit Grade 3 or higher cytopenias for several weeks following TECARTUS infusion. Monitor complete blood counts. ( 5.6 ) Hypogammaglobulinemia: Monitor and provide replacement therapy. ( 5.7 )

Secondary

Malignancies: T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies. In the event that a secondary malignancy occurs after treatment with TECARTUS, contact Kite at 1-844-454-KITE (5483). ( 5.8 )

5.1 Cytokine Release Syndrome CRS, including fatal or life-threatening reactions, occurred following treatment with TECARTUS. CRS occurred in 91% (75/82) of patients with MCL, including ≥ Grade 3 (Lee grading system 1 ) CRS in 18% of patients. Among the patients with MCL who died after receiving TECARTUS, one patient had a fatal CRS event. The median time to onset of CRS was three days (range: 1 to 13 days) and the median duration of CRS was ten days (range: 1 to 50 days) for patients with MCL. CRS occurred in 92% (72/78) of patients with ALL, including ≥ Grade 3 (Lee grading system 1 ) CRS in 26% of patients. Three patients with ALL had ongoing CRS events at the time of death. The median time to onset of CRS was five days (range: 1 to 12 days) and the median duration of CRS was eight days (range: 2 to 63 days) for patients with ALL. The incidence of CRS (first occurrence) within the first 7 days after TECARTUS infusion was 83% (68/82) in patients with MCL and 90% (70/78) in patients with ALL. In all patients combined (MCL/ALL), the incidence of first CRS (first occurrence) within the first 7 days after TECARTUS infusion was 86% (138/160). Among patients with CRS, the key manifestations (&gt;10%) were similar in MCL and ALL and included fever (93%), hypotension (62%), tachycardia (59%), chills (32%), hypoxia (31%), headache (21%), fatigue (20%), and nausea (13%). Serious events associated with CRS in MCL and ALL combined (≥ 2%) included hypotension, fever, hypoxia, tachycardia, and dyspnea <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> . Confirm that a minimum of two doses of tocilizumab are available for each patient prior to infusion of TECARTUS. Monitor patients daily for at least 7 days following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 2 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time <span class="opacity-50 text-xs">[see Patient Counseling Information (17) ]</span> . At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.2 Neurologic Toxicities Neurologic toxicities (including ICANS) that were fatal or life-threatening, occurred following treatment with TECARTUS. Neurologic events occurred in 81% (66/82) of patients with MCL, including ≥ Grade 3 in 37% of patients. The median time to onset for neurologic events was six days (range: 1 to 32 days) with a median duration of 21 days (range: 2 to 454 days) in patients with MCL. Neurologic events occurred in 87% (68/78) of patients with ALL, including ≥ Grade 3 in 35% of patients. The median time to onset for neurologic events was 7 days (range: 1 to 51 days) with a median duration of 15 days (range: 1 to 397 days) in patients with ALL. For patients with MCL, 54 (66%) patients experienced CRS before the onset of neurological events. Five (6%) patients did not experience CRS with neurologic events and eight patients (10%) developed neurological events after the resolution of CRS. Neurologic events resolved for 119 out of 134 (89%) patients treated with TECARTUS. Nine patients (three patients with MCL and six patients with ALL) had ongoing neurologic events at the time of death. For patients with ALL, neurologic events occurred before, during, and after CRS in 4 (5%), 57 (73%), and 8 (10%) of patients; respectively. Three patients (4%) had neurologic events without CRS. The onset of neurologic events can be concurrent with CRS, following resolution of CRS or in the absence of CRS. The incidence of neurologic events (first occurrence) within the first 7 days after TECARTUS infusion was 56% (46/82) in patients with MCL and 55% (43/78) in patients with ALL. In all patients combined (MCL/ALL) the incidence of neurologic events (first occurrence) within the first 7 days after TECARTUS infusion was 56% (89/160). Ninety-one percent of all treated patients experienced the first CRS or neurological event within the first 7 days after TECARTUS infusion. The most common neurologic events (&gt;10%) were similar in MCL and ALL and included encephalopathy (57%), headache (37%), tremor (34%), confusional state (26%), aphasia (23%), delirium (17%), dizziness (15%), anxiety (14%), and agitation (12%). Serious events (≥ 2%) including encephalopathy, aphasia, confusional state, and seizures occurred after treatment with TECARTUS. Monitor patients daily for at least 7 days following infusion for signs and symptoms of neurologic toxicity/ICANS. Monitor patients for signs or symptoms of neurologic toxicities for 2 weeks after infusion and treat promptly <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . Advise patients to avoid driving for at least 2 weeks following infusion.

5.3 Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS), including life-threatening reactions, occurred following treatment with TECARTUS. HLH/MAS occurred in 4% (3/78) of patients with ALL. Two patients experienced Grade 3 events and 1 patient experienced a Grade 4 event. The median time to onset for HLH/MAS was 8 days (range: 6 to 9 days) with a median duration of 5 days (range: 2 to 8 days). All three patients with HLH/MAS had concurrent CRS symptoms and neurologic events after TECARTUS infusion. Treatment of HLH/MAS should be administered per institutional standards.

5.4 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, may occur due to dimethyl sulfoxide (DMSO) or residual gentamicin in TECARTUS.

5.5 Severe Infections Severe or life-threatening infections occurred in patients after TECARTUS infusion. Infections (all grades) occurred in 56% (46/82) of patients with MCL and 44% (34/78) of patients with ALL.

Grade

3 or higher infections, including bacterial, viral, and fungal infections, occurred in 30% of patients with ALL and MCL. TECARTUS should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after TECARTUS infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines. Febrile neutropenia was observed in 6% of patients with MCL and 35% of patients with ALL after TECARTUS infusion and may be concurrent with CRS. The febrile neutropenia in 27 (35%) of patients with ALL includes events of "febrile neutropenia" (11 (14%)) plus the concurrent events of "fever" and "neutropenia" (16 (21%)). In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated. In immunosuppressed patients, life-threatening and fatal opportunistic infections have been reported. The possibility of rare infectious etiologies (e.g., fungal and viral infections such as HHV-6 and progressive multifocal leukoencephalopathy) should be considered in patients with neurologic events and appropriate diagnostic evaluations should be performed. Hepatitis B Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines before collection of cells for manufacturing.

5.6 Prolonged Cytopenias Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and TECARTUS infusion. In patients with MCL, Grade 3 or higher cytopenias not resolved by Day 30 following TECARTUS infusion occurred in 55% (45/82) of patients and included thrombocytopenia (38%), neutropenia (37%), and anemia (17%). In patients with ALL who were responders to TECARTUS treatment, Grade 3 or higher cytopenias not resolved by Day 30 following TECARTUS infusion occurred in 20% (7/35) of the patients and included neutropenia (12%) and thrombocytopenia (12%); Grade 3 or higher cytopenias not resolved by Day 60 following TECARTUS infusion occurred in 11% (4/35) of the patients and included neutropenia (9%) and thrombocytopenia (6%). Monitor blood counts after TECARTUS infusion.

5.7 Hypogammaglobulinemia B cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with TECARTUS. Hypogammaglobulinemia was reported in 16% (13/82) of patients with MCL and 9% (7/78) of patients with ALL. Monitor immunoglobulin levels after treatment with TECARTUS and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following TECARTUS treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least six weeks prior to the start of lymphodepleting chemotherapy, during TECARTUS treatment, and until immune recovery following treatment with TECARTUS.

5.8 Secondary Malignancies Patients treated with TECARTUS may develop secondary malignancies. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies. Mature T cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes. <span class="opacity-50 text-xs">[see Boxed Warning , Adverse Reactions (6.3) , Patient Counseling Information (17) ]</span>. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.