Afamitresgene Autoleucel

1 INDICATIONS AND USAGE TECELRA is a melanoma-associated antigen A4-(MAGE-A4)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive and whose tumor expresses the MAGE-A4 antigen as determined by FDA-approved or cleared companion diagnostic devices. This indication is approved under accelerated approval based on overall response rate and durability of response [see Clinical Studies ( 14 )]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. TECELRA is a melanoma-associated antigen A4 (MAGE-A4)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive and whose tumor expresses the MAGE-A4 antigen as determined by FDA-approved or cleared companion diagnostic devices. This indication is approved under accelerated approval based on overall response rate and duration of response ( 14 ). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

12.1 Mechanism of Action TECELRA is a genetically modified autologous T cell immunotherapy consisting of CD4 and CD8 positive T cells transduced with a self-inactivating LV to express an affinity- enhanced TCR specific for human MAGE-A4 on the cell surface. The TCR recognizes an HLA-A*02 restricted MAGE-A4 peptide. MAGE-A4 is an intracellular cancer-testis antigen that has restricted expression in normal tissues and is expressed in synovial sarcoma. Antigen-specific activation of TECELRA via TCR- peptide-HLA-A*02 complex results in T cell proliferation, cytokine secretion, and killing of MAGE-A4/HLA-A*02 expressing synovial sarcoma cells.

2 DOSAGE AND ADMINISTRATION For autologous use only. For intravenous use only. For autologous use only. For intravenous use only. Prior to infusion Verify patient's identity prior to infusion ( 2.2 ). Administer a lymphodepleting regimen of cyclophosphamide and fludarabine ( 2.2 ). Premedicate with acetaminophen and an H1-antihistamine ( 2.2 ). TECELRA Dose and Administration The recommended dose is between 2.68 x 10 9 to 10 x 10 9 MAGE-A4 T cell receptor (TCR) positive T cells ( 2.1 ). Administer each infusion bag within one hour of thawing. DO NOT USE a leukodepleting filter ( 2.2 ). DO NOT USE prophylactic systemic corticosteroids ( 2.2 ). 2.1 Recommended Dose The recommended dose is between 2.68 x 10 9 to 10 x 10 9 MAGE-A4 T cell receptor (TCR) positive T cells administered as a single intravenous infusion. TECELRA is provided as a single dose for infusion in one or more infusion bag(s). Verify the number of bags received for the indicated dose prior to preparation for infusion. 2.2 Preparation and Administration Receipt of TECELRA Plan for TECELRA to arrive prior to beginning lymphodepleting chemotherapy. Ensure storage conditions in vapor phase of liquid nitrogen (≤ -130°C). TECELRA is shipped directly to the healthcare facility in the vapor phase of a liquid nitrogen shipper. Upon receipt of TECELRA confirm the patient's identifiers on the metal cassette and product bag. Inspect the product for obvious signs of damage and contact 1-855-246-9232 if any anomalies are identified at the time of receipt. Transfer TECELRA in the original packaging, containing the cassette(s) protecting the infusion bag(s), to onsite storage at ≤ -130°C before the shipper expires. Store TECELRA in a manner that is consistent with How Supplied/Storage and Handling ( 16 ) . If unforeseen circumstances prevent proper storage of TECELRA consistent with How Supplied/Storage and Handling ( 16 ) , contact 1-855-246-9232 to arrange for return shipment. Preparing Patient for TECELRA Administration Confirm availability of TECELRA at the healthcare facility prior to starting the lymphodepleting chemotherapy regimen. Match the patient's identity with the patient identifiers on the TECELRA cassette(s) and infusion bag(s). Do not infuse TECELRA if the information on the patient-specific label(s) does not match the intended patient. Administer a lymphodepleting chemotherapy regimen of fludarabine 30 mg/m 2 /day intravenously for 4 days starting on the seventh day before TECELRA infusion (Day-7 to Day -4) and cyclophosphamide 600 mg/m 2 /day intravenously for 3 days starting the seventh day before TECELRA infusion (Day -7 to Day -5). Refer to fludarabine prescribing for information on fludarabine dosage in patients with renal impairment. Short-acting or pegylated granulocyte-colony stimulating factor (G-CSF) may be administered at the discretion of the physician, and according with institutional standards, from 24 hours after last day of lymphodepleting chemotherapy (from Day -3) until resolution of neutropenia. Premedication Premedicate with an H1-antihistamine and acetaminophen according to institutional standard practice, approximately 30-60 minutes prior to TECELRA infusion. Avoid prophylactic systemic corticosteroids, as it may interfere with the activity of TECELRA. Preparation of TECELRA for Administration Do not thaw the product until it is ready to be used. Coordinate the timing of TECELRA thaw and infusion. Confirm infusion time in advance and adjust the start time of TECELRA thaw such that it will be available for infusion when the patient is ready. A TECELRA dose may be contained in one or more infusion bag(s). Verify the number of bags received for the indicated dose prior to preparation of TECELRA for infusion. If more than one bag will be infused for the treatment dose, thaw and administer the contents of each infusion bag completely before proceeding to thaw and infuse the contents of the next infusion bag. 1. Confirm patient identity. Prior t

6 ADVERSE REACTIONS Most common adverse reactions (≥ 20%) were, cytokine release syndrome, nausea, vomiting, fatigue, infections, pyrexia, constipation, dyspnea, abdominal pain, non-cardiac chest pain, decreased appetite, tachycardia, back pain, hypotension, diarrhea, and edema. Grade 3 or 4 laboratory abnormalities (≥20%) were lymphocyte count decreased, neutrophil count decreased, white cell blood count decreased, red blood cell decreased, and platelet count decreased ( 6.1 ). The most common serious adverse reactions (≥ 5%) were cytokine release syndrome and pleural effusion ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact USWM CT, LLC at 1-855-246-9232 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 this section reflects the exposure to TECELRA in 44 patients with advanced synovial sarcoma treated in the SPEARHEAD-1 clinical trial (Cohort 1). Patients with synovial sarcoma received TECELRA across a dose of 2.68 x 10 9 to 10 x 10 9 MAGE-A4 TCR positive T cells [see Clinical Studies ( 14 )]. Serious adverse reactions occurred in 52% of patients with synovial sarcoma. The most common serious adverse reactions (occurring in ≥ 5%) included CRS (9%) and pleural effusion (7%). Table 1 summarizes adverse reactions that occurred in at least 10% of patients. Table 1. Adverse Reactions Occurring in ≥10% of Patients in SPEARHEAD-1 (Cohort 1) SOC Grouped Term (N=44) All Grades n (%) Grade ≥ 3 n (%) Investigations Weight decreased 5 (11) 1 (2) Gastrointestinal disorders Nausea 29 (66) 1 (2) Vomiting 16 (36) 0 (0) Constipation 14 (32) 0 (0) Abdominal pain 11 (25) 2 (5) Diarrhea 9 (21) 0 (0) General disorders and administration site conditions Fatigue 15 (34) 0 (0) Pyrexia 14 (32) 2 (5) Non-cardiac chest pain 10 (23) 1 (2) Chills 7 (16) 0 (0) Edema 9 (21) 0 (0) Asthenia 7 (16) 1 (2) Chest pain 6 (14) 0 (0) Immune system disorders Cytokine Release Syndrome As per American Society for Transplantation and Cellular Therapy (ASTCT) criteria 1 33 (75) 1 (2) Infections and infestations Any infection Any infection includes all infection terms under the 'Infections and infestations' System Organ Class 14 (32) 6 (14) Nervous system disorders Headache 8 (18) 1 (2) Dizziness 5 (11) 0 (0) Metabolism and nutrition disorders Decreased appetite 10 (23) 1 (2) Musculoskeletal and connective tissue disorders Back pain 9 (21) 2 (5) Pain in extremity 6 (14) 0 (0) Respiratory, thoracic, and mediastinal disorders Dyspnea 11 (25) 2 (5) Cough 8 (18) 0 (0) Vascular disorders Hypotension 9 (21) 0 (0) Hypertension 7 (16) 1 (2) Cardiac disorders Sinus Tachycardia/ Tachycardia 9 (21) 0 (0) Skin and subcutaneous tissue disorders Alopecia 6 (14) 0 (0) Other clinically important adverse reactions occurring in patients receiving TECELRA include Grade 1 ICANS reported in one patient (2%). Table 2. Laboratory Abnormalities Abnormalities are laboratory values that were considered an adverse event Worsened from Baseline in ≥10% of Patients in SPEARHEAD-1 (Cohort 1) Laboratory Abnormalities N=44 All Grades n (%) Grade 3 or 4 n (%) Grading based on NCI CTCAE version 5.0. Lymphocyte count decreased 43 (98) 43 (98) Neutrophil count decreased 42 (96) 40 (91) White blood cell decreased 42 (96) 38 (86) Red blood cell decreased 42 (96) 14 (32) Platelet count decreased 36 (82) 9 (21) Alanine aminotransferase increased 20 (46) 2 (5)

5 WARNINGS AND PRECAUTIONS Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) : Monitor for ICANS events for at least 4 weeks after treatment with TECELRA ( 5.2 ). Prolonged Severe Cytopenia : Patients may exhibit severe cytopenia (hemoglobin < 8.0 g/dL, neutrophils < 1,000/mm 3 , platelets < 50,000/mm 3 ) for several weeks following lymphodepleting chemotherapy and TECELRA infusion. Monitor blood counts prior to and after TECELRA infusion ( 5.3 ). Infections : Monitor patients for signs and symptoms of infection; treat appropriately ( 5.4 ). Secondary Malignancies : In the event that a secondary malignancy occurs after treatment with TECELRA, contact 1-855-246-9232 ( 5.5 ). Hypersensitivity Reactions : Monitor for hypersensitivity reactions during infusion ( 5.6 ). Effects on Ability to Drive and Use Machines : Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, for at least 4 weeks after receiving TECELRA ( 5.2 ). 5.1 Cytokine Release Syndrome Cytokine release syndrome (CRS), including potentially life-threatening reaction has been observed following administration of TECELRA. CRS occurred in 75% of patients, 2% of whom had Grade ≥ 3 CRS. The median time to onset was 2 days (range: 1 to 5 days) and the median time to resolution was 3 days (range: 1 to 14 days). The most common symptoms were fever (97%), tachycardia (52%), hypotension (30%), nausea/vomiting (21%) and headache (15%) [see Adverse Reactions ( 6 )] . Management for CRS (including Grade 1) was tocilizumab (55%). Thirteen patients received one dose and five patients received more than one dose. Of the five patients who received more than one dose of tocilizumab, two patients received dexamethasone in addition to tocilizumab. Ensure that healthcare providers administering TECELRA have immediate access to medications and resuscitative equipment to manage CRS. Ensure patients are euvolemic prior to initiating the infusions. During and following TECELRA administration, closely monitor patients for signs and symptoms of CRS. Following treatment with TECELRA, monitor patients for at least 7 days at the healthcare facility for CRS. Continue to monitor patients for CRS for at least 4 weeks following treatment with TECELRA. Counsel patients to seek medical attention should signs or symptoms of CRS occur. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care based on severity and consider further management per current practice guidelines. 5.2 Immune Effector Cell-associated Neurotoxicity Syndrome Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) has been observed following administration of TECELRA. One patient (2%) had Grade 1 ICANS. Time to onset was two days and time to resolution was one day. Symptoms included mild mental status changes. Other symptoms may include disorientation to time and place, mild drowsiness, mild inattention. Severe symptoms may include altered level of consciousness, seizures, cerebral edema, impairment of cognitive skills, progressive aphasia, motor weakness. Ensure that healthcare providers administering TECELRA have immediate access to medications and resuscitative equipment to manage ICANS. During and following TECELRA administration, closely monitor patients for signs and symptoms of ICANS. Following treatment with TECELRA, monitor patients for at least 7 days at the healthcare facility for ICANS. Continue to monitor patients for ICANS for at least 4 weeks following treatment with TECELRA. Counsel patients to seek medical attention should signs or symptoms of ICANS occur. At the first sign of ICANS, immediately evaluate patients for hospitalization and institute treatment with supportive care based on severity and consider further management per current practice guidelines. Effect on Ability to Drive and Use Machines Due to the potential for neurologic

4 CONTRAINDICATIONS DO NOT use TECELRA in adults who are heterozygous or homozygous for HLA- A*02:05P. DO NOT use TECELRA in adults who are heterozygous or homozygous for HLA-A*02:05P ( 4 ).