Axicabtagene ciloleucel

12.1 Mechanism of Action YESCARTA, 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.

1 INDICATIONS AND USAGE YESCARTA is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of: Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy. ( 1.1 ) Adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. ( 1.1 ) Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). ( 1.2 ) 1.1 Large B-cell Lymphoma YESCARTA is indicated for the treatment of: Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy. Adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. 1.2 Follicular Lymphoma YESCARTA is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate [see Clinical Studies (14.2) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

2 DOSAGE AND ADMINISTRATION For autologous use only. For intravenous use only. Do NOT use a leukodepleting filter. ( 2.2 ) Administer a lymphodepleting regimen of cyclophosphamide and fludarabine before infusion of YESCARTA. ( 2.2 ) Verify the patient's identity prior to infusion. ( 2.2 ) Premedicate with acetaminophen and an H1-antihistamine. ( 2.2 ) Confirm availability of tocilizumab prior to infusion. ( 2.2 , 5.1 ) Dosing of YESCARTA is based on the number of chimeric antigen receptor (CAR)-positive viable T cells. ( 2.1 ) The target YESCARTA 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 ) 2.1 Dose For autologous use only. For intravenous use only. Each single infusion bag of YESCARTA contains a suspension of chimeric antigen receptor (CAR)-positive T cells in approximately 68 mL. 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. 2.2 Administration YESCARTA is for autologous use only. The patient's identity must match the patient identifiers on the YESCARTA cassette and infusion bag. Do not infuse YESCARTA if the information on the patient-specific label does not match the intended patient. Preparing Patient for YESCARTA Infusion Confirm availability of YESCARTA prior to starting the lymphodepleting regimen. Pre-treatment Administer a lymphodepleting chemotherapy regimen of cyclophosphamide 500 mg/m 2 intravenously and fludarabine 30 mg/m 2 intravenously on the fifth, fourth, and third day before infusion of YESCARTA. Premedication Administer acetaminophen 650 mg PO and diphenhydramine 12.5 mg intravenously or PO approximately 1 hour before YESCARTA infusion. Consider the use of prophylactic corticosteroid in patients after weighing the potential benefits and risks [see Warnings and Precautions (5.1 and 5.2) ] . Preparation of YESCARTA for Infusion Coordinate the timing of YESCARTA thaw and infusion. Confirm the infusion time in advance, and adjust the start time of YESCARTA thaw such that it will be available for infusion when the patient is ready. Confirm patient identity: Prior to YESCARTA preparation, match the patient's identity with the patient identifiers on the YESCARTA cassette. Do not remove the YESCARTA product bag from the cassette if the information on the patient-specific label does not match the intended patient. Once patient identification is confirmed, remove the YESCARTA product bag from the cassette and check that the patient information on the cassette label matches the bag label. Inspect the product 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 YESCARTA 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 YESCARTA in new medium prior to infusion. Once thawed, YESCARTA 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 infusion and during the recovery period. Do NOT use a leukodepleting filter. Central venous access is recommended for the infusion of YESCARTA. Confirm the patient's identity matches the patient identifiers on the YESCARTA product bag. Prime the tubing with normal saline prior to infusion. Infuse the entire contents of the YESCARTA bag within 30 minutes by either gravity or a peristaltic pump. YESCARTA is stable at room temperature for up to 3 hours after thaw. Gently agitate the product bag during YESCARTA infusion to prevent cell clumping. After the entire content of the product bag is infused, rinse the tubing with normal saline at the same infusion rate to ensure all product is delivered. YESCARTA contains human blood cells that are genetically modified with replication incompetent retroviral vector. Follow universal precautions and local biosafety guidelines for handling and disposal to avoid potential transmission of infectious diseases. Monitoring Monitor patients at least daily for 7 days following infusion for signs and symptoms of CRS and neurologic toxicities. 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 [see Warnings and Precautions (5.1) ] . Evaluate for and treat other causes of fe

6 ADVERSE REACTIONS The most common adverse reactions (incidence ≥ 30%), excluding laboratory abnormalities, in patients with non-Hodgkin lymphoma are CRS, fever, hypotension, encephalopathy, fatigue, tachycardia, headache, nausea, febrile neutropenia, diarrhea, musculoskeletal pain, infections with pathogen unspecified, chills and decreased appetite. ( 6.1 ) The most common Grade 3-4 laboratory abnormalities (≥ 30%) are leukopenia, lymphopenia, neutropenia, anemia, thrombocytopenia, and hypophosphatemia. ( 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. The safety data described in the WARNINGS AND PRECAUTIONS and in the ADVERSE REACTIONS sections reflect exposure to a single dose of YESCARTA in four clinical studies, including 168 patients with relapsed or refractory LBCL (Study 1), 108 patients with relapsed or refractory LBCL (Study 2), 146 patients with relapsed or refractory iNHL (including 124 with FL; Study 3), and 13 patients with relapsed or refractory primary CNS lymphoma (PCNSL) (Study 4). Relapsed or Refractory Large B-cell Lymphoma Study 1 The safety of YESCARTA was evaluated in Study 1, a randomized, open-label, multicenter study in which patients with primary refractory LBCL or first relapse of LBCL received YESCARTA (N = 168) or standard therapy (N = 168) [see Clinical Studies (14) ] . Patients had not yet received treatment for relapsed or refractory lymphoma and were potential candidates for autologous HSCT. The trial excluded patients who were not deemed candidates for transplant or who had a history of central nervous system (CNS) disorders (such as seizures or cerebrovascular ischemia), serious or uncontrolled infection, or autoimmune disease requiring systemic immunosuppression. The study required ANC ≥ 1000/mm 3 , platelet count ≥ 75,000/mm 3 , creatinine clearance ≥ 60 ml/min, AST/ALT ≤ 2.5 × ULN, and total bilirubin ≤ 1.5 mg/dL. The median age of the YESCARTA-treated safety population was 59 years (range: 21 to 80 years); 62% were male. The baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 54% of patients and 1 in 46%. Serious adverse reactions occurred in 50% of patients. The most common serious adverse reactions (> 5%) included CRS, fever, encephalopathy, hypotension, infection with unspecified pathogen, and pneumonia. Fatal adverse reactions occurred in 2% of patients. Sixty-seven percent (112/168) of patients received tocilizumab after infusion of YESCARTA. Table 3 summarizes selected non-laboratory adverse reactions in patients treated with YESCARTA, and Table 4 summarizes selected new or worsening Grade 3 or 4 laboratory abnormalities. Table 3. Adverse Reactions in ≥ 10% of Patients with Relapsed or Refractory LBCL in Study 1 Adverse Reaction YESCARTA N = 168 Any Grade (%) Grade 3 or Higher (%) Blood and Lymphatic System Disorder Febrile neutropenia 31 31 Cardiac Disorders Tachycardia Represents a composite of multiple, related preferred terms. 43 2 Arrhythmia 14 3 Gastrointestinal Disorders Diarrhea Diarrhea includes diarrhea, colitis. 42 3 Nausea 40 2 Abdominal pain 20 4 Constipation 20 0 Vomiting 20 0 Dry Mouth 10 0 General Disorders and Administration Site Conditions Fever 93 9 Fatigue 52 7 Chills 28 1 Edema 23 1 Immune System Disorders Cytokine release syndrome CRS includes coagulopathy, tachycardia, arrhythmia, cardiac failure, diarrhea, nausea, vomiting, fever, fatigue, chills, edema, decreased appetite, musculoskeletal pain, headache, tremor, dizziness, renal insufficiency, cough, hypoxia, dyspnea, pleural effusion, respiratory failure, rash, hypotension, and hypertension. 92 7 Hypogammaglobulinemia 11 0 Infections and Infestations Infections with pathogen unspecified 25 8 Viral infections 15 4 Bacterial infections 10 5 Fungal infections 10 1 Metabolism and Nutrition Disorders Decreased appetite 24 4 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 40 1 Motor dysfunction Motor dysfunction includes muscle contractions involuntary, muscle spasms, muscle twitching, muscular weakness. 15 4 Nervous System Disorders Encephalopathy Encephalopathy includes encephalopathy, altered state of consciousness, amnesia, apraxia, bradyphrenia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, dysarthria, dysgraphia, dyspraxia, lethargy, loss of consciousness, memory impairment, mental impairment, mental status changes, metabolic encephalopathy, slow speech, somnolence, toxic encephalopathy. 46 18 Headache 41 3 Tremor 25 1 Dizziness 25 4 Aphasia 20 7 Neuropathy peripheral 11 2 Psychiatric Disorders Insomnia 13 0 Deli