Lifileucel

Risk Summary

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.

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 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.

No carcinogenicity or genotoxicity studies have been conducted with lifileucel. No studies have been conducted to evaluate the effects of lifileucel on fertility.

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
• Prolonged Severe Cytopenia
• Internal Organ Hemorrhage
• Severe Infection
• Cardiac Disorder
• Respiratory Failure
• Acute Renal Failure
• Hypersensitivity Reactions

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 lifileucel 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 lifileucel. 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 lifileucel 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 lifileucel (N=156):

Adverse Reactions occurred from lifileucel 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 lifileucel 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 Lifileucel (N=156):

Frequency of Grade 3 or 4 laboratory abnormalities from lifileucel 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 lifileucel regimen, there were 12 deaths (7.5%), including 2 deaths during the lymphodepleting period, 6 deaths within 30 days following lifileucel administration, and additional 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 arrythmia, extensive ascites and liver injury and bone marrow failure.