LIFILEUCEL: 198 Adverse Event Reports & Safety Profile

AMTAGVI (lifileucel) is a tumor-derived autologous T cell immunotherapy comprised of a suspension of tumor-derived T cells for intravenous infusion. AMTAGVI is manufactured from resected patient tumor tissue prosected from one or more tumor lesions. Immune cells derived from a patient's tumor(s) are expanded in cell culture, washed, formulated as a cell suspension, and cryopreserved. The product must pass a sterility test before release for shipping as a frozen suspension in 1 to 4 patient-specific infusion bag(s) in individual protective metal cassettes. The product is thawed prior to administration back into the same patient [see Dosage and Administration (2.2) , How Supplied/Storage and Handling (16) ] . AMTAGVI is composed primarily of T cells of the CD4+T and CD8+T cell lineages. AMTAGVI may also contain monocytes and other lymphocytes, including B cells and NK cells. AMTAGVI may contain viable melanoma tumor cells from the original tumor tissue used to manufacture the product. The formulation contains 48% PlasmaLyte A, 50% CryoStor CS10 (resulting in final concentration of 5% dimethyl sulfoxide (DMSO)), 2% of 25% human serum albumin (resulting in a final concentration of 0.5% albumin), and 300 IU/mL IL-2 (aldesleukin). A single dose of AMTAGVI is provided in 1 to 4 infusion bag(s) containing 100 mL to 125 mL of viable cells per bag in individual protective cassettes.

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 )

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 identifiers on the AMTAGVI cassette label. Do not remove the AMTAGVI infusion bag from the cassette if the patient identifiers on the AMTAGVI cassette label do not match the intended patient.

Contact Iovance

Biotherapeutics, Inc. at 1-833-400-IOVA if there are any discrepancies. Once recipient identification on the cassette is confirmed, remove the AMTAGVI infusion bag from the cassette. Check that the patient identifiers on the cassette label match the patient identifiers on the AMTAGVI infusion bag label and match the recipient's identity with the patient identifiers on the AMTAGVI infusion bag label.

Contact Iovance

Biotherapeutics, Inc. at 1-833-400-IOVA if there are any discrepancies. Inspect each bag for any breaks or cracks prior to thawing. Inspect the spike ports for any damage prior to thawing. If a bag is damaged or compromised, do not infuse the contents and contact Iovance Biotherapeutics, Inc. at 1-833-400-IOVA. For thawing, place the infusion bag inside a second sealable bag (preferably sterile) per local guidelines in case of a leak and to protect ports from contamination. Thaw AMTAGVI at approximately 35°C to 39°C using either a water bath or a dry thaw method until there is no visible ice or frozen contents in the infusion bag. Total time from start of thaw until completion of thawing should be no more than 10 minutes. Immediately remove bag from thawing device. Remove the infusion bag from the sealable plastic bag and wipe dry. Do not wash, spin down, or resuspend AMTAGVI in new media prior to infusion. Once thawed, administer each bag of AMTAGVI as soon as possible. If needed, AMTAGVI may be maintained at room temperature (18°C to 25°C) not to exceed 3 hours. Do not re-freeze or refrigerate thawed product. Prior to infusion, inspect the contents of the thawed infusion bag. If cell clumps are visible, gently mix the contents of the bag by inverting the bag prior to infusion. If needed, gently massage the bag to disperse cell clumps. Do not infuse the contents of an infusion bag if it is damaged or leaking, or otherwise appears to be compromised. Infusion of AMTAGVI Before infusion, the patient's health status should be reassessed and confirmed to be acceptable prior to AMTAGVI and IL-2 administration. Confirm the patient's identity matches with the patient identifiers on the infusion bag. Do NOT use a leukocyte depleting filter with AMTAGVI. Prime the tubing with normal saline prior to infusion. Initiate the infusion. Infuse the entire contents of each bag as soon as possible but within 3 hours of thawing. Administer AMTAGVI at an infusion rate of approximately 1 mL per minute for the initial 5 minutes; thereafter 5 mL to 10 mL per minute. Contents of all bags must be infused to complete a single dose. After the last bag is infused, rinse the tubing with normal saline at the same infusion rate to ensure all product is delivered. AMTAGVI contains human cells. Follow universal and local biosafety guidelines applicable for the handling and disposal of AMTAGVI to avoid potential transmission of infectious diseases. Administration of IL-2 (aldesleukin)

Beginning

3 to 24 hours after AMTAGVI infusion, administer intravenous IL-2 (aldesleukin) at 600,000 IU/kg every 8 to 12 hours for up to a maximum of 6 doses to support cell expansion in vivo . IL-2 (aldesleukin) should be administered in an inpatient setting under the supervision of a physician experienced in the use of anticancer agents.

None. None ( 4 )

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 <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> . 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 pathogen specified Infection with mentioned pathogen includes bacteremia, candida infection, clostridium difficile colitis, cytomegalovirus infection or reactivation, Epstein-Barr virus infection, escherichia bacteremia, fungal skin infection, herpes simplex, herpes zoster, metapneumovirus infection, oral herpes, oral candidiasis, pneumonia klebsiella, respiratory syncytial virus infection, skin candida, tuberculosis. 19 (12.2) 6 (3.8) Metabolism and nutrition disorders Decreased appetite 48 (30.8) 2 (1.3) Nervous system disorders Headache 33 (21.2) 1 (0.6)

Encephalopathy

Encephalopathy includes encephalopathy, automatism, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, hypersomnia, lethargy, leukoencephalopathy, memory impairment, mental status changes, paranoia, somnolence, and stupor. 27 (17.3) 9 (5.8) Renal and urinary disorders Acute kidney injury Acute kidney injury includes acute kidney injury, anuria, azotemia, renal failure, renal tubular dysfunction, renal tubular necrosis, oliguria, and blood creatinine increased. 31 (19.9) 11 (7.1)

Hematuria

22 (14.1) 2 (1.3) Respiratory, thoracic and mediastinal disorders Hypoxia Hypoxia includes hypoxia and oxygen saturation decreased. 37 (23.7) 19 (12.2)

Dyspnea

Dyspnea includes dyspnea, acute respiratory failure, orthopnea, respiratory distress, respiratory failure, and dyspnea exertional 34 (21.8) 13 (8.3) Skin and subcutaneous tissue disorders Rash Rash includes rash, rash generalized, rash maculo-papular, rash papular, rash pruritic, rash erythematous, and rash macular. 58 (37.2) 15 (9.6)

Alopecia

48 (30.8) 0 (0)

Pruritus

21 (13.5) 0 (0) Vascular disorders Hypotension Hypotension includes hypotension, blood pressure decreased, blood pressure systolic decreased, blood pressure diastolic decreased, and orthostatic hypotension. 58 (37.2) 17 (10.9) Capillary leak syndrome 21 (13.5) 7 (4.5)

Hypertension

Hypertension includes hypertension, blood pressure increased, blood pressure systolic increased, and blood pressure diastolic increased. 21 (13.5) 11 (7.1) Adverse reactions that occurred in less than 10% of patients treated with AMTAGVI included the following: Eye disorders: Uveitis (4.5%). Other eye disorders included Grade 1 or 2 retinal detachment, vision blurred, visual impairment, periorbital edema, visual acuity reduced, and retinal hemorrhage. Immune system disorders: Infusion related reaction (6.4%), anaphylactic reaction (1.3%), and cytokine release syndrome (3.2%). Skin and subcutaneous tissue disorders: Vitiligo (7.1%).

Table

2: Grade 3 or 4 Laboratory Abnormalities Occurring in at Least 10% of Melanoma Patients Following Treatment with AMTAGVI (N=156)

Laboratory Abnormality Grades

3 or 4 (%) Frequency of Grade 3 or 4 laboratory abnormalities from AMTAGVI infusion to 6 months (182 days) post infusion.

Thrombocytopenia

122 (78.2)

Neutropenia

108 (69.2)

Anemia

91 (58.3)

Leukopenia

73 (46.8)

Lymphopenia

66 (42.3)

Hypophosphatemia

40 (25.6)

Serious Adverse Reactions

Serious adverse reactions leading to death included acute respiratory failure (n=1), renal failure (n=2), cardiac arrhythmia (n=1), severe infections (n=4) including sepsis and septic shock, pneumonia, and encephalitis, internal organ hemorrhage (n=2), ascites and liver injury (n=1) and bone marrow failure (n=1).

Deaths Among

160 patients with unresectable, or metastatic melanoma who initiated the AMTAGVI regimen, there were 12 deaths (7.5%), including 2 deaths during the lymphodepleting period, 6 deaths within 30 days following AMTAGVI administration, and additional 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 and liver injury and bone marrow failure.

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 is indicated, or patient is deemed ineligible for IL-2 (aldesleukin) infusion.

5.7 Acute Renal Failure Patients treated with AMTAGVI may develop worsened renal function which has been associated with deaths. Monitor patients with signs and symptoms of acute renal failure before and after AMTAGVI infusion. Withhold or discontinue AMTAGVI if severe acute renal injury is indicated, or patient is deemed ineligible for IL-2 (aldesleukin) infusion.

5.8 Hypersensitivity Reactions Allergic reactions including serious hypersensitivity (e.g., anaphylaxis) may occur with the infusion of AMTAGVI. Acute infusion reactions (defined as occurring within 1 day of infusion) may occur and include fever, rigors or chills, tachycardia, rash, hypotension, dyspnea, cough, chest tightness, and wheezing. These events generally resolve on the same day of infusion. Patients should be monitored during and after infusion for signs and symptoms of a severe reaction, and treated promptly.