Background
Phase II single-arm multicenter trial (C-144-01), pooled cohorts 2 and 4, N=153 evaluable, unresectable/metastatic melanoma progressing after anti-PD-1 ± anti-CTLA-4 and BRAF/MEK inhibitors (if BRAF-mutated). Required tumor resection (≥1.5 cm lesion) for TIL manufacturing; lifileucel infused after non-myeloablative lymphodepletion then high-dose IL-2. Enrolled 2014–2020 (US/EU/AU). Median 3.0 prior lines (81.7% had both anti-PD-1 and anti-CTLA-4).
Interventions and follow up
Treatment: Tumor resection for TIL manufacturing → non-myeloablative lymphodepletion (cyclophosphamide + fludarabine) → single lifileucel infusion → high-dose IL-2 (up to 6 doses); pooled cohorts 2 and 4 (N=153)
Primary endpoint: ORR by independent review (RECIST 1.1)
mFollow up: 27.6 mo
Primary endpoint: ORR by independent review (RECIST 1.1)
mFollow up: 27.6 mo
Results
ORR: 31.4% (95% CI 24.1–39.4%); 8 CR + 40 PR (N=153)
mDOR: not reached; 41.7% of responses maintained ≥18 mo
mOS: 13.9 mo
mPFS: 4.1 mo
Subgroup (normal LDH + target lesion SOD <median): significantly higher ORR (multivariable analysis)
mDOR: not reached; 41.7% of responses maintained ≥18 mo
mOS: 13.9 mo
mPFS: 4.1 mo
Subgroup (normal LDH + target lesion SOD <median): significantly higher ORR (multivariable analysis)
Adverse events
Grade 3/4 (lymphodepletion/IL-2-driven): thrombocytopenia 76.9%, anemia 50.0%, febrile neutropenia 41.7%, neutropenia 38.6%
High-dose IL-2 AEs: hypotension, fluid overload (vascular leak syndrome) — managed inpatient
Lifileucel-attributable immune grade 3/4: uncommon; cytopenias resolved with supportive care
Treatment-related death: 2 (1.3%)
High-dose IL-2 AEs: hypotension, fluid overload (vascular leak syndrome) — managed inpatient
Lifileucel-attributable immune grade 3/4: uncommon; cytopenias resolved with supportive care
Treatment-related death: 2 (1.3%)
Conclusions
Lifileucel produced a clinically meaningful ORR of 31.4% with durable responses (mDOR not reached, 41.7% lasting ≥18 mo) in heavily pretreated advanced melanoma refractory to both anti-PD-1 and anti-CTLA-4, providing durable benefit in a population with no remaining standard systemic options.
Key Limitations
Single-arm without randomized comparator — ORR not comparable to historical controls. Complex ~22-day vein-to-vein manufacturing requires resectable lesions and centralized GMP facilities. High-dose IL-2 requires inpatient administration with intensive monitoring — limiting delivery to specialized centers. mOS 13.9 mo reflects the heavily pretreated, high-burden population; only ~31% respond. Elevated LDH and high tumor burden correlate with lower response. Adoption requires infrastructure unavailable at most centers.
Clinical Context
FDA granted accelerated approval for lifileucel (Amtagvi) in February 2024 for unresectable/metastatic melanoma after prior anti-PD-1 and, if BRAF V600-mutant, a BRAF inhibitor — the first FDA-approved TIL cell therapy and first cellular immunotherapy for solid tumors. Distinct from CAR-T (antigen-agnostic autologous TILs targeting polyclonal neoantigens); reserved for later-line ICI-refractory disease. Manufacturing time, logistics, and IL-2 administration limit current uptake to academic centers with TIL programs.