Brexucabtagene Autoleucel

1 INDICATIONS AND USAGE 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). Adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). 1.1 Mantle Cell Lymphoma TECARTUS is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL). 1.2 Acute Lymphoblastic Leukemia TECARTUS is indicated for the treatment of adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

12.1 Mechanism of Action TECARTUS, a CD19-directed genetically modified autologous T cell immunotherapy, binds to CD19-expressing cancer cells and normal B cells. Studies demonstrated that following anti-CD19 CAR T cell engagement with CD19-expressing target cells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signaling cascades that lead to T cell activation, proliferation, acquisition of effector functions, and secretion of inflammatory cytokines and chemokines. This sequence of events leads to killing of CD19-expressing cells.

2 DOSAGE AND ADMINISTRATION 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 For autologous use only. For intravenous use only. 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'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 3 hours. Administration For autologous use only. Confirm that tocilizumab and emergency equipment are available prior to

6 ADVERSE REACTIONS The most common non-laboratory adverse reactions (incidence greater than or equal to 20%) are: MCL: CRS, fever, encephalopathy, hypotension, infection with pathogen unspecified, viral infections, fatigue, tachycardias, chills, hypoxia, tremor, cough, musculoskeletal pain, nausea, edema, headache, constipation, diarrhea, decreased appetite, dyspnea, rash, insomnia, pleural effusion, aphasia, motor dysfunction. 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. Study 1 (Relapsed/Refractory Mantle Cell Lymphoma) Cohort 1 and 2 The safety of TECARTUS in patients with relapsed/refractory Mantle cell lymphoma (MCL) was evaluated in a single-arm study (Study 1; Cohorts 1 and 2) in which a total of 82 patients received a single dose of TECARTUS (2 × 10 6 or 0.5 × 10 6 anti-CD19 CAR T cells/kg) [see Clinical Studies (14.1) ] . The most common serious adverse reactions (> 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. Table 3 summarizes the adverse reactions that occurred in at least 10% of patients in Study 1 Cohorts 1 and 2 and Table 4 lists the laboratory abnormalities of Grade 3 or 4 that occurred in at least 10% of patients in Study 1 Cohorts 1 and 2. Table 3. Adverse Reactions Observed in at Least 10% of Patients in Study 1 (Cohorts 1 and 2) (N=82) Adverse Reaction Any Grade (%) Grade ≥3 (%) Blood and Lymphatic System Disorders Coagulopathy Includes multiple related terms. 10 2 Cardiac Disorders Tachycardias 45 0 Bradycardias 10 0 Non-ventricular Arrhythmias 10 4 Gastrointestinal Disorders Nausea 35 1 Constipation 29 0 Diarrhea 28 5 Abdominal pain 17 0 Oral pain 16 0 Vomiting 13 0 Dysphagia 10 2 General Disorders and Administration Site Conditions Fever 94 15 Fatigue 48 1 Chills 41 0 Edema 35 2 Pain 17 2 Immune System Disorders Cytokine release syndrome 91 18 Hypogammaglobulinemia 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 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 35 1 Aphasia 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 18 9 Urine output decreased 11 1 Respiratory, Thoracic and Mediastinal Disorders Hypoxia 40 20 Cough 38 0 Dyspnea 24 6 Pleural effusion 21 5 Skin and Subcutaneous Tis

5 WARNINGS 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 Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with TECARTUS. CRS occurred in 93% (157/168) of patients with MCL, including ≥ Grade 3 (Lee 2014 grading system 1 ) CRS in 12% of patients in Study 1. Among the patients with MCL who died after receiving TECARTUS, 1 patient had a fatal CRS event. The median time to onset of CRS was 4 days (range: 1 to 13 days). The median duration of CRS was 7 days (range: 1 to 50 days). 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 5 days (range: 1 to 12 days) and the median duration of CRS was 8 days (range: 2 to 63 days) for patients with ALL. Confirm that a minimum of 2 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. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated [see Dosage and Administration (2.3) ] . 5.2 Neurologic Toxicities Neurologic toxicities (including ICANS), which may be severe, life-threatening or fatal, occurred following treatment with TECARTUS. Neurologic events occurred in 80% (135/168) of patients with MCL, including ≥ Grade 3 in 33% of patients in Study 1. The median time to onset for neurologic events was 6 days (range: 1 to 32 days). The median duration of neurologic events was 19 days (range: 1 to 828 days). 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 105 (63%) patients experienced CRS before the onset of neurological events. Six (4%) patients did not experience CRS with neurologic events and 25 patients (15%) developed neurological events after the resolution of CRS. Neurologic events resolved for 167 out of 203 (82%) patients treated with TECARTUS. Fourteen patients (8 patients with MCL and 6 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. 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 [see Dosage and Administration

4 CONTRAINDICATIONS None. None. ( 4 )