Lifileucel

1 INDICATIONS AND USAGE AMTAGVI is a tumor-derived autologous T cell immunotherapy indicated for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor. This indication is approved under accelerated approval based on objective response rate (ORR) [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). AMTAGVI is a tumor-derived autologous T cell immunotherapy indicated for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor. This indication is approved under accelerated approval based on objective response rate (ORR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s) ( 1 )

12.1 Mechanism of Action The specific mechanism of action of AMTAGVI (lifileucel) is unknown.

2 DOSAGE AND ADMINISTRATION For autologous use only. For intravenous use only. Verify the patient's identity prior to infusion. For autologous use only. For intravenous use only. Verify the patient's identity prior to infusion. Administer AMTAGVI in an inpatient hospital setting with an intensive care facility ( 2.1 ) The AMTAGVI dose is between 7.5 × 10 9 and 72 × 10 9 viable cells ( 2.1 ) Administer a lymphodepleting regimen before infusion of AMTAGVI ( 2.2 ) Do NOT use a leukocyte depleting filter with AMTAGVI ( 2.2 ) Premedicate the patient with acetaminophen, or equivalent, and diphenhydramine, or another H1-antihistamine ( 2.2 ) Avoid prophylactic use of systemic corticosteroids ( 2.2 ) Administer entire dose of AMTAGVI ( 2.2 ) Administer IL-2 (aldesleukin) after infusion of AMTAGVI ( 2.2 ) See Full Prescribing Information for instructions on receipt, preparation, and administration of AMTAGVI ( 2.2 , 16 ) 2.1 Dose Administer in an inpatient hospital setting under the supervision of a physician experienced in the use of anticancer agents. An intensive care facility and specialists skilled in cardiopulmonary or intensive care medicine must be available. AMTAGVI is provided as a single dose for infusion containing a suspension of tumor-derived T cells. The dose is supplied in 1 to 4 patient-specific IV infusion bag(s) in individual protective metal cassettes. Each dose contains 7.5 × 10 9 to 72 × 10 9 viable cells. 2.2 Administration AMTAGVI is for autologous use only. The patient's identity must match the patient identifiers on the AMTAGVI cassette(s) and infusion bag(s). Preparing Patient for AMTAGVI Infusion Confirm availability of AMTAGVI and IL-2 (aldesleukin) prior to starting the lymphodepleting regimen. Pretreatment Administer a lymphodepleting chemotherapy regimen of cyclophosphamide 60 mg/kg intravenously with mesna daily for 2 days followed by fludarabine 25 mg/m 2 intravenously daily for 5 days before infusion of AMTAGVI. Infuse AMTAGVI as soon as possible after 24 hours have elapsed following the last dose of fludarabine, but no later than 4 days. Premedication Pre-medicate the patient with acetaminophen and diphenhydramine or another H1-antihistamine, approximately 30 to 60 minutes prior to AMTAGVI infusion. Avoid prophylactic use of systemic corticosteroids which may interfere with the activity of AMTAGVI. Receipt of AMTAGVI AMTAGVI is shipped directly to the treatment center in the vapor phase of a liquid nitrogen cryoshipper. All treatment centers should have onsite storage in vapor phase of liquid nitrogen. Product and patient-specific labels are located on both the product infusion bag(s) and protective metal cassette(s), which are inside the liquid nitrogen cryoshipper. Match the identity of the patient with the patient identifiers on the cassette(s) and infusion bag(s) upon receipt. Confirm the number of AMTAGVI cassette(s) and infusion bag(s) matches the total number of cassettes and infusion bags on the shipment packing slip. Store AMTAGVI frozen in the vapor phase of liquid nitrogen (less than or equal to minus 150°C). Administration of AMTAGVI The AMTAGVI dose is contained in 1 to 4 cryopreserved patient-specific infusion bag(s) in individual protective metal cassette(s). Thaw and infuse 1 bag at a time if more than 1 bag has been provided. Wait to thaw the next bag until the previous bag has been safely and completely administered. Preparation of AMTAGVI Do not thaw the product until it is ready to be infused. Coordinate the timing of AMTAGVI thaw and infusion. Confirm the infusion time in advance and adjust the start time for thaw so that AMTAGVI is available for infusion when the patient is ready. Once 1 bag of AMTAGVI is thawed, the infusion should be started as soon as possible and must be completed within 3 hours at room or ambient temperature (18°C to 25°C). Confirm the availability of IL-2 (aldesleukin). Prior to AMTAGVI preparation, match the recipient's identity with the patient identifie

6 ADVERSE REACTIONS The most common (incidence of greater than or equal to 20%) non-laboratory adverse reactions in order of decreasing frequency were chills, pyrexia, fatigue, tachycardia, diarrhea, febrile neutropenia, edema, rash, hypotension, alopecia, infection, hypoxia, and dyspnea. The serious adverse reactions included: Treatment-Related Mortality [see Warnings and Precautions (5.1) ] Prolonged Severe Cytopenia [see Warnings and Precautions (5.2) ] Internal Organ Hemorrhage [see Warnings and Precautions (5.3) ] Severe Infection [see Warnings and Precautions (5.4) ] Cardiac Disorder [see Warnings and Precautions (5.5) ] Respiratory Failure [see Warnings and Precautions (5.6) ] Acute Renal Failure [see Warnings and Precautions (5.7) ] Hypersensitivity Reactions [see Warnings and Precautions (5.8) ] The most common (incidence of greater than or equal to 20%) non-laboratory adverse reactions in order of decreasing frequency were chills, pyrexia, fatigue, tachycardia, diarrhea, febrile neutropenia, edema, rash, hypotension, alopecia, infection, hypoxia, and dyspnea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Iovance Biotherapeutics, Inc. at 1-833-400-IOVA (4682) 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 pooled safety data described in this section reflect exposure to AMTAGVI within a regimen that included cyclophosphamide, fludarabine, and IL-2 (aldesleukin) in the global, multicenter, multicohort, open-label, single-arm clinical study in which 156 adult patients with unresectable or metastatic melanoma received a single infusion of AMTAGVI [see Clinical Studies (14) ] . The median age of the study population was 56 years (range: 20 to 79 years); 53.8% were men. The performance status prior to tumor procurement was 68.6% with ECOG 0 and 31.4% with ECOG 1. Table 1 summarizes the adverse reactions that occurred in at least 10% of patients treated with AMTAGVI and Table 2 describes the laboratory abnormalities of Grade 3 or 4 that occurred in at least 10% of patients. Table 1: Adverse Reactions Observed in at Least 10% of Melanoma Patients Treated with AMTAGVI (N=156) Adverse Reaction Any Grade n (%) Grade 3 or Higher n (%) Adverse Reactions occurred from AMTAGVI infusion to 6 months (182 days) post infusion. Blood and lymphatic system disorders Febrile neutropenia 73 (46.8) 73 (46.8) Cardiac disorders Tachycardia Tachycardia includes tachycardia and sinus tachycardia, atrial fibrillation, supraventricular tachycardia. 74 (47.4) 12 (7.7) Gastrointestinal disorders Diarrhea 73 (46.8) 3 (1.9) Vomiting 68 (43.6) 2 (1.3) Nausea 107 (68.6) 4 (2.6) General disorders and administration site conditions Chills 118 (75.6) 8 (5.1) Pyrexia 95 (60.9) 16 (10.3) Fatigue Fatigue includes fatigue, asthenia, and malaise. 87 (55.8) 8 (5.1) Edema Edema includes edema, face edema, generalized edema, localized edema, edema peripheral, peripheral swelling, edema genital, scrotal edema, brain edema, catheter site edema, conjunctival edema, eyelid edema, laryngeal edema, macular edema, periorbital edema, pulmonary edema, vasogenic cerebral edema, and lymphoedema. 66 (42.3) 8 (5.1) Investigations Weight increased 30 (19.2) 2 (1.3) Infections and Infestations 42 (26.9) 21 (13.5) Infection with pathogen unspecified Infection with unspecified pathogen includes cellulitis, conjunctivitis, cystitis, dermatitis infected, device related infection, diarrhea infectious, endocarditis, enterocolitis infectious, infection, meningitis, nasopharyngitis, neutropenic sepsis, pneumonia, pyuria, rash pustular, respiratory tract infection (RTI), rhinitis, sepsis, sinusitis, skin infection, urinary tract infection (UTI). 30 (19.2) 17 (10.9) Infection with path

5 WARNINGS AND PRECAUTIONS Hypersensitivity reactions: Monitor for hypersensitivity reactions during infusion ( 5.8 ) 5.1 Treatment-Related Mortality AMTAGVI is associated with treatment-related mortality. In the clinical trial, the treatment-related mortality rate was 7.5% (N=160), including 2 deaths during the lymphodepleting period, 6 deaths within 30 days, and 4 deaths 38 to 150 days following AMTAGVI administration. Adverse reactions associated with these deaths included severe infections (sepsis, pneumonia and encephalitis), internal organ hemorrhage (abdominal hemorrhage and intracranial hemorrhage), acute renal failure, acute respiratory failure, cardiac arrythmia, extensive ascites, liver injury, and bone marrow failure. Because clinical trials are conducted under widely varying conditions, treatment-related mortality rates observed in the clinical trials of a drug may not reflect the rates observed in practice. 5.2 Prolonged Severe Cytopenia Patients treated with AMTAGVI may exhibit Grade 3 or higher cytopenia for weeks or longer. Based on adverse event reporting, Grade 3 or higher cytopenia or pancytopenia which did not resolve to less than or equal to Grade 2 or lasted beyond 30 days post AMTAGVI infusion occurred in 45.5% of melanoma patients who received AMTAGVI. Prolonged cytopenia included thrombocytopenia (30.1%), lymphopenia (19.9%), neutropenia (17.3%), leukopenia (14.7%), and pancytopenia (1.3%). Monitor blood counts after AMTAGVI infusion. 5.3 Internal Organ Hemorrhage Patients treated with AMTAGVI may exhibit internal organ hemorrhage. Intraabdominal and intracranial hemorrhage can be life-threatening and have been associated with at least two deaths in patients who received AMTAGVI. Withhold or discontinue AMTAGVI infusion if internal organ hemorrhage is indicated, or patient is deemed ineligible for IL-2 (aldesleukin) infusion. Patients with persistent or repeated thrombocytopenia after receiving AMTAGVI should not use anticoagulants or must be under close monitoring if the patient must take anticoagulants. 5.4 Severe Infection Severe, life-threatening, or fatal infections occurred in patients after AMTAGVI infusion. AMTAGVI treatment-related infections (any severity) occurred in 26.9% of patients with melanoma. Grade 3 or higher infections occurred in 13.5% of patients, including 10.9% of patients with infections of an unspecified pathogen and 3.8% of patients with infections of a specified pathogen. Do not administer AMTAGVI to patients with clinically significant systemic infections. Monitor patients for signs and symptoms of infection before and after AMTAGVI infusion and treat appropriately. Administer prophylactic antimicrobials according to institutional guidelines. Febrile neutropenia was observed in 46.8% of patients with melanoma after AMTAGVI Infusion. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated. 5.5 Cardiac Disorder Patients treated with AMTAGVI may exhibit cardiac disorder. Grade 3 or higher cardiac disorders related to the AMTAGVI regimen occurred in 9.0% (14/156) of patients who received AMTAGVI including tachycardia, atrial fibrillation, arrhythmia, acute myocardial infarction, cardiac ventricular thrombosis, cardiomyopathy, QT-prolongation. Cardiac arrhythmia resulted in one death among melanoma patients who received AMTAGVI. Monitor patients with signs and symptoms of cardiac disorder before and after AMTAGVI infusion. Withhold or discontinue AMTAGVI infusion, if severe cardiac disorder is indicated, or patient is deemed ineligible for IL-2 (aldesleukin) infusion. 5.6 Respiratory Failure Patients treated with AMTAGVI may develop worsened respiratory function which has been associated with deaths. Monitor patients with signs and symptoms of respiratory failure before and after AMTAGVI infusion. Withhold or discontinue AMTAGVI infusion if severe acute respiratory failure i

4 CONTRAINDICATIONS None. None ( 4 )