Lifileucel Sustains Long-Term Responses and Survival in Advanced Melanoma

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One-time lifileucel (Amtagvi), a tumor-infiltrating lymphocyte cell therapy, generated durable responses and favorable 5-year overall survival (OS) outcomes in patients with pretreated, advanced melanoma, according to the final analysis of the phase 2 C-144-01 study (NCT02360579) presented at the 2025 ASCO Annual Meeting.1

The objective response rate (ORR) was 31.4%; 5.9% and 25.5% of patients had complete responses (CR) and partial responses (PR), respectively. Of note, 79.3% of patients experienced tumor burden reduction. In total, 16 patients had deepened responses, defined as SD that improved to PR or PR that improved to CR; 4 patients had a PR more than 1 year after lifileucel infusion that deepened to CR as late as 3 years following infusion. Additionally, the median independent review committee (IRC)–assessed duration of response was 36.5 months (95% CI, 8.3-not reached [NR]), and 31.3% (n = 15/48) of responders completed the 5-year assessment with ongoing responses.

“One-time lifileucel therapy resulted in durable and deepening responses in patients with advanced melanoma who have limited treatment options after immune checkpoint inhibitor [ICI] therapy,” lead study author Theresa Medina, MD, an associate professor in the Department of Medicine-Medical Oncology at the University of Colorado Anschutz School of Medicine in Aurora, said in a presentation of the data. “Lifileucel demonstrated a long-term treatment benefit in patients with advanced melanoma previously treated with ICIs, with [approximately] 20% of patients remaining alive at 5 years.”

Background and C-144-01 Study Design

In February 2024, lifileucel was granted accelerated approval by the FDA for the treatment of patients with unresectable or metastatic melanoma who had previously received a PD-1 antibody, including those with BRAF V600–positive disease who had received a BRAF inhibitor with or without a MEK inhibitor.2 This marked the first approval of a cellular therapy for the treatment of patients with unresectable or metastatic melanoma. The regulatory decision was supported by data from the C-144-01 study.

The prospective, interventional multicenter study evaluated lifileucel in patients at least 18 years of age with unresectable or metastatic melanoma (stage IIIc or IV) who experienced disease progression on at least 1 prior systemic therapy, which included a PD-1 antibody, as well as a BRAF inhibitor with or without a MEK inhibitor for patients with BRAF V600E disease.3 Patients were also required to have at least 1 measurable target lesion per RECIST 1.1 criteria, at least 1 resectable lesion of at least 1.5 cm in diameter after resection to generate TILs, and an ECOG performance status of 0 or 1 with a life expectancy of 3 months or longer. Of note, patients were required to meet specific hematologic parameters, which consisted of an absolute neutrophil count of 1000/mm3 or greater, hemoglobin levels of 9.0 g/dL or greater, and platelet counts of 100,000/mm3 or greater.

The primary end point was ORR; secondary end points included duration of response (DOR), disease control rate, progression-free survival, overall survival (OS), and safety.

Baseline Patient Characteristics

At the data cutoff date of November 20, 2024, the median follow-up was 57.8 months.1 In the pooled population of cohorts 2 and 4, the median age was 56 years (range, 20-79), 54.2% of patients were male, and 68.0% of patients had an ECOG performance status of 0. At study entry, 93.5% of patients had stage IV melanoma, and 26.8% of patients had a BRAF V600E/V600K mutation. Moreover, PD-L1 tumor proportion scores included 1% or greater (49.7%) and less than 1% (20.9%). LDH levels included less than 1 (45.8%), 1 to 2 (35.3%), and 2 or greater (19.0%).

Additionally, most patients had 3 or more baseline target and nontarget lesions (75.8%) and baseline target lesions in 3 or more anatomic sites (71.2%). Liver and/or brain lesions by IRC were observed in 47.1% of patients. The median sum of the diameters of target lesions was 101.1 mm (range, 13.5-552.9), and the median number of prior systemic therapies was 3 (range, 1-9). Prior BRAF/MEK inhibitor therapy was reported in 25.5% of patients, prior anti–CTLA-4 therapy was reported in 81.7% of patients, and prior anti–CTLA-4 plus anti–PD-L1 therapy was reported in 53.6% of patients. Notably, 71.2% and 26.8% of patients had primary and secondary resistance, respectively, to anti–PD-1/PD-L1 therapy by SITC criteria. The median cumulative duration of anti–PD-1/PD-L1 therapy was 7.0 months (range, 0.7-75.8).

Additional Efficacy and Safety Data With Lifileucel

The median IRC-assessed DOR was 36.5 months (95% CI, 8.3-NR). The median OS was 13.9 months, and the estimated 5-year OS rate was 19.7%.

Of note, the adverse effects (AEs) reported with lifileucel were consistent with nonmyeloablative lymphodepletion and interleukin-2 safety profiles and rapidly declined within 2 weeks after lifileucel infusion. Most grade 3 or 4 cytopenias resolved to grade 2 or lower by day 30. Furthermore, most red blood cell and platelet transfusions occurred during the first 14 days after the initiation of nonmyeloablative lymphodepletion.

“This final 5-year analysis of the C-144-01 trial is the longest prospective follow-up of lifileucel and of any drug in the second-line setting for ICI-resistant melanoma,” Medina concluded in the presentation.

Disclosures: Medina reported receiving institutional research funding from Agenus, Bristol-Myers Squibb, Day One Biopharmaceuticals, Genentech, Immunocore, Iovance Biotherapeutics, Merk, Moderna Therapeutics, Pfizer, Regeneron, Replimune, TriSalus Life Sciences, and Ultimovacs.

References

1. Medina T, Chesney JA, Kluger HM, et al. Long-term efficacy and safety of lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in patients with advanced melanoma: a 5-year analysis of the C-144-01 study. J Clin Oncol. 2025;43(suppl 16):9515. doi: 10.1200/JCO.2025.43.16_suppl.9515
2. FDA approves first cellular therapy to treat patients with unresectable or metastatic melanoma. FDA. February 16, 2024. Accessed June 2, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-unresectable-or-metastatic-melanoma
3. Study of lifileucel (LN-144), autologous tumor infiltrating lymphocytes, in the treatment of patients with metastatic melanoma (LN-144). ClinicalTrials.gov. Updated November 26, 2024. Accessed June 2, 2025. https://www.clinicaltrials.gov/study/NCT02360579