Lifileucel (Monograph)

Brand name: Amtagvi
Drug class: Cellular Therapy

Introduction

Lifileucel is a tumor-derived autologous T cell immunotherapy.

Uses for Lifileucel

Lifileucel has the following uses:

Lifileucel is 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).

Lifileucel has been designated an orphan drug by FDA for the treatment of malignant melanoma stages IIb to IV.

Lifileucel is a suspension of tumor-derived T cells manufactured from resected patient tumor tissue. Immune cells derived from a patient's tumor(s) are expanded in cell culture, washed, formulated as a cell suspension, and cryopreserved.

Efficacy of lifileucel was evaluated in an open-label single-arm clinical study in patients with unresectable or metastatic melanoma who had previously been treated with at least one systemic therapy, including a PD-1 blocking antibody, and if BRAF V600 mutation-positive, a BRAF inhibitor or BRAF inhibitor with MEK inhibitor. Lifileucel was administered following a lymphodepleting regimen, and IL-2 (aldesleukin) was administered 3 to 24 hours after the lifileucel infusion to support cell expansion in vivo. The median administered lifileucel dose was 21.1× 10⁹ viable cells. A total of 73 patients received lifileucel at the recommended dose and were included in the primary efficacy analysis. The objective response rate (ORR) among the efficacy population was 31.5% (complete response [CR] in 3 patients and partial response [PR] in 20 patients). The median duration of response was not reached. Among responders, 56.5%, 47.8%, and 43.5% maintained durable responses at 6, 9, and 12 months, respectively. In a supporting pooled efficacy analysis which included 153 patients treated with lifileucel at a median dose of 21.1 x 10⁹ viable cells, ORR was 31.4% (CR in 8 patients and PR in 40 patients). Among responders, 62.5%, 56.3% and 54.2% maintained durable responses at 6, 9, and 12 months, respectively. Median duration of response was not reached at a median follow-up of 27.6 months.

Lifileucel Dosage and Administration

General

Lifileucel is available in the following dosage form(s) and strength(s):

• Lifileucel is a cell suspension for IV infusion

• A single dose of lifileucel contains 7.5 × 10⁹ to 72 × 10⁹ viable cells suspended in 1 to 4 patient-specific infusion bag(s)

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

For autologous use only. For IV only.

Verify the patient's identity prior to infusion.

• Administer lifileucel in an inpatient hospital setting with an intensive care facility.

• Confirm availability of lifileucel and IL-2 (aldesleukin) prior to starting the lymphodepleting regimen.

• The lifileucel dose is between 7.5 × 10⁹ and 72 × 10⁹ viable cells.

• Administer a lymphodepleting regimen before infusion of lifileucel.

• Do NOT use a leukocyte depleting filter with lifileucel.

• Premedicate the patient with acetaminophen, or equivalent, and diphenhydramine, or another H1-antihistamine approximately 30 to 60 minutes prior to infusion of lifileucel.

• Avoid prophylactic use of systemic corticosteroids.

• Infuse the entire contents of each bag of lifileucel to complete a single dose. Administer at an infusion rate of approximately 1 mL per minute for the initial 5 minutes; thereafter 5 mL to 10 mL per minute.

• Administer IL-2 (IV aldesleukin) 3 to 24 hours after infusion of lifileucel.

• See Full Prescribing Information for instructions on receipt, preparation, and administration of lifileucel.

Cautions for Lifileucel

Contraindications

None

Warnings/Precautions

Treatment-related Mortality

Lifileucel 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 lifileucel 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 arrhythmia, 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.

Prolonged Severe Cytopenia

Patients treated with lifileucel 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 lifileucel infusion occurred in 45.5% of melanoma patients who received lifileucel. Prolonged cytopenia included thrombocytopenia (30.1%), lymphopenia (19.9%), neutropenia (17.3%), leukopenia (14.7%), and pancytopenia (1.3%). Monitor blood counts after lifileucel infusion.

Internal Organ Hemorrhage

Patients treated with lifileucel 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 lifileucel. Withhold or discontinue lifileucel 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 lifileucel should not use anticoagulants or must be under close monitoring if the patient must take anticoagulants.

Severe Infection

Severe, life-threatening, or fatal infections occurred in patients after lifileucel infusion. Lifileucel 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 lifileucel to patients with clinically significant systemic infections. Monitor patients for signs and symptoms of infection before and after lifileucel infusion and treat appropriately. Administer prophylactic antimicrobials according to institutional guidelines.

Febrile neutropenia was observed in 46.8% of patients with melanoma after lifileucel infusion. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.

Cardiac Disorder

Patients treated with lifileucel may exhibit cardiac disorder. Grade 3 or higher cardiac disorders related to the lifileucel regimen occurred in 9.0% (14/156) of patients who received lifileucel including tachycardia, atrial fibrillation, arrhythmia, acute myocardial infarction, cardiac ventricular thrombosis, cardiomyopathy, and QT-prolongation. Cardiac arrhythmia resulted in one death among melanoma patients who received lifileucel.

Monitor patients with signs and symptoms of cardiac disorder before and after lifileucel infusion. Withhold or discontinue lifileucel infusion, if severe cardiac disorder is indicated, or patient is deemed ineligible for IL-2 (aldesleukin) infusion.

Respiratory Failure

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

Acute Renal Failure

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

Hypersensitivity Reactions

Allergic reactions including serious hypersensitivity (e.g., anaphylaxis) may occur with the infusion of lifileucel.

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.

Specific Populations

Pregnancy

There are no available data with lifileucel use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with lifileucel. Therefore, lifileucel is not recommended for women who are pregnant, and pregnancy after lifileucel 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.

Lactation

There is no information regarding the presence of lifileucel 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 lifileucel and any potential adverse effects on the breastfed infant from lifileucel or from the underlying maternal condition.

Females and Males of Reproductive Potential

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 lifileucel.

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

Pediatric Use

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

Geriatric Use

Of 156 patients with unresectable or metastatic melanoma who were treated with lifileucel 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.

Common Adverse Effects

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.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

The specific mechanism of action of lifileucel is unknown.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information).

• Advise patients of the signs and symptoms associated with hypersensitivity reactions including fever, rigors or chills, tachycardia, rash, hypotension, dyspnea, cough, chest tightness, and wheezing.

• Advise patients of the signs or symptoms associated with bone marrow suppression (i.e., neutropenia, thrombocytopenia and anemia) for more than several weeks following lymphodepleting chemotherapy and lifileucel.

• Advise patients of the signs and symptoms associated with severe infections. Advise patients that lifileucel treatment regimen will not be initiated if they have an ongoing uncontrolled infection. Anti-microbial prophylaxis and treatment of infection will be administered.

• Advise patients of the signs or symptoms of internal organ hemorrhage following lifileucel treatment regimen. Advise patients to seek immediate medical attention should signs or symptoms of internal organ hemorrhage occur at any time.

• Advise patients of the signs or symptoms of cardiopulmonary or renal injuries following lifileucel treatment regimen. Advise patients to seek immediate medical attention should signs or symptoms of cardiopulmonary, or renal injury occur at any time.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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