AMTAGVI (Lifileucel)

Melanoma accounts for less than 2% of all skin cancers as well as all cancer deaths in the United States. However, melanoma may spread quickly; therefore, early diagnosis and treatment are important for improved cure rates. The 5-year survival rates are 99.6% for localized melanomas, 73.9% with regional spread, and 35.1% with distant metastases. Advanced melanoma, also known as unresectable or metastatic disease, are typically treated with immunotherapy with immune checkpoint inhibitors (e.g., ipilimumab, cemiplimab, nivolumab, pembrolizumab) and, if BRAF V600 mutation positive, a BRAF inhibitor (e.g., encorafenib, vemurafenib, dabrafenib) with or without a MEK inhibitor (e.g., trametinib, cobimetinib, binimetinib). Immunotherapies have an initial response rate of about 45% with a relapse rate of 10%, and BRAF/MEK inhibitors effectively shrinking tumors but are associated with higher relapse rates due to resistance. For continued progressive disease, chemotherapy is an option but it demonstrates a limited response rates of 4% to 10% and a median overall survival rate of approximately 7 months. On February 16, 2024, the FDA approved lifileucel (Amtagvi), which is the first 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) with continued approval contingent upon verification and description of clinical benefit in a confirmatory trial. The efficacy and safety of lifileucel (Amtagvi) was evaluated in a multi-center, open-label, single-arm clinical study. Enrolled patients had unresectable or metastatic melanoma previously treated with at least one systemic immunotherapy (i.e., immune checkpoint inhibitors), and if BRAF V600 mutation-positive, a BRAF inhibitor with or without a MEK inhibitor. Excluded patients included those with uncontrolled brain metastases, organ allograft or prior cell transfer, melanoma of uveal or ocular origin, systemic steroid therapy for any reason, Grade 2 or higher hemorrhage within 14 days prior to study enrollment (tumor resection), LVEF less than 45% or NYHA functional classification greater than Class 1, and patients with FEV1 of less than or equal to 60%. There were 111 patients who underwent tumor resection with 22 patients not receiving therapy with lifileucel and 89 patients receiving lifileucel therapy. Of the 89 patients receiving lifileucel therapy, seven were excluded due to product specification/comparability, leaving 82 patients for efficacy evaluation. Among these, 73 patients received the full recommended dosing range of 7.5 x 109 to 72 x 109 viable cells. The median age was 58 years (range: 25-74 years), and 52.1% were male. As for race, 94.5% were white, 2.7% were black, and 1.4% were Asian. The median target lesion sum of diameters was 108.7 mm (range: 15.7-552.9 mm), and the performance status prior to tumor procurement was ECOG 0 (71.2%) and ECOG 1 (28.8%). Lifileucel was administered following a lymphodepleting regimen consisting of cyclophosphamide 60 mg/kg daily with mesna for 2 days followed by fludarabine 25 mg/m2 daily for 5 days. Three to 24 hours after the lifileucel infusion, patients received IL-2 (aldesleukin) at 600,000 IU/kg every 8 to 12 hours for up to 6 doses in order to support cell expansion. The median time to initial response with lifileucel was 1.5 months (range: 1.3- 4.2 months). <a id="