AMTAGVI Suspension for intravenous infusion Ref.[108367] Active ingredients: Lifileucel

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.

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)]

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 Reactions occurred from AMTAGVI infusion to 6 months (182 days) post infusion.
^a Tachycardia includes tachycardia and sinus tachycardia, atrial fibrillation, supraventricular tachycardia.
^b Fatigue includes fatigue, asthenia, and malaise.
^c 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.
^d1 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).
^d2 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.
^e 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.
^f Acute kidney injury includes acute kidney injury, anuria, azotemia, renal failure, renal tubular dysfunction, renal tubular necrosis, oliguria, and blood creatinine increased.
^g Hypoxia includes hypoxia and oxygen saturation decreased.
^h Dyspnea includes dyspnea, acute respiratory failure, orthopnea, respiratory distress, respiratory failure, and dyspnea exertional
ⁱ Rash includes rash, rash generalized, rash maculo-papular, rash papular, rash pruritic, rash erythematous, and rash macular.
^j Hypotension includes hypotension, blood pressure decreased, blood pressure systolic decreased, blood pressure diastolic decreased, and orthostatic hypotension. k Hypertension includes hypertension, blood pressure increased, blood pressure systolic increased, and blood pressure diastolic increased.

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):

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

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.

Risk Summary

There are no available data with AMTAGVI use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with AMTAGVI. Therefore, AMTAGVI is not recommended for women who are pregnant, and pregnancy after AMTAGVI administration should be discussed with the treating physician. Report pregnancies to Iovance Biotherapeutics, Inc. at 1-833-400-IOVA.

In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Risk Summary

There is no information regarding the presence of AMTAGVI in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AMTAGVI and any potential adverse effects on the breastfed infant from AMTAGVI or from the underlying maternal condition.

Pregnancy Testing

The pregnancy status of women of child-bearing potential should be verified. Sexually active females of reproductive potential should have a pregnancy test prior to starting treatment with AMTAGVI.

Infertility

There are no data on the effect of AMTAGVI on fertility.

The safety and efficacy of AMTAGVI have not been established in pediatric patients.

Of 156 patients with unresectable or metastatic melanoma who were treated with AMTAGVI in clinical studies, 37 patients (23.7%) were 65 years of age or older. No differences in safety or effectiveness were observed between elderly patients and younger patients.