Lifileucel Is Explored in Metastatic Melanoma at ICE-T 2025

When patients with advanced melanoma progress following treatment with immune checkpoint inhibitors (ICIs) and targeted agents, adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) offers a potentially tailored immunotherapeutic approach, according to a presentation by Muhammad Umair Mushtaq, MD, during the 2025 Immune Cell Effector Therapy Conference.¹ The therapy is currently undergoing evaluation.

“Patients progressing after ICI and targeted therapies represent a critical unmet need,” Mushtaq said in an interview with Targeted Therapies in Oncology. “TIL therapy offers a tailored, potent alternative.” Mushtaq is an associate professor of medicine in the Division of Hematologic Malignancies and Cellular Therapeutics, Department of Medicine, at the University of Kansas Medical Center in Kansas City. Mushtaq highlighted updated findings from a phase 2 (NCT06151847) trial² evaluating lifileucel (Amtagvi) in combination with reduced-dose fludarabine and cyclophosphamide for lymphodepletion followed by IL-2 in patients with unresectable or metastatic melanoma.

The trial evaluated 153 patients previously treated with ICIs and BRAF/MEK inhibitors and demonstrated an overall response rate (ORR) of 31% in 48 patients. The median duration of response (DOR) was not reached (NR). The overall survival (OS) rates after 1, 2, 3, and 4 years were 54%, 34%, 28%, and 22%, respectively.² Patients were stratified as early responders, late responders, responders with deepened response, responders without deepened response, and all responders.

The OS rates at 4 years were 48.3% (95% CI, 31.9%-62.9%) for early responders, 41.7% (95% CI, 10.9%-63.9%) for late responders, 68.2% (39.5%85.4%) for responders with deepened response, 37.2% (95% CI, 21.0%-53.5%) for responders without deepened response, and 47.3% (95% CI, 32.5%60.7%) for all responders, respectively. The median DORs were NR (95% CI, 6.1-NR), 19.8 months (95% CI, 4.1-NR), NR (95% CI, 8.3-NR), 26.2 months (95% CI, 4.1-NR), and NR (95% CI, 8.30-NR), respectively.

Key inclusion criteria include unresectable or metastatic melanoma with disease progression after 1 or more lines of therapy. Patients receive fludarabine (30 mg/m2) and cyclophosphamide (750 mg/m²), and TIL infusion followed by high-dose IL-2.

The primary end point will be to determine TIL persistence. Secondary end points include ORR, DOR, progression-free survival (PFS), and OS. Exploratory objectives will evaluate correlative analysis to characterize the tumor microenvironment.

2025 ASCO Annual Meeting

Previously, the phase 2 C-144-01 study (NCT02360579) revealed that lifileucel led to durable responses and a favorable 5-year OS outcome, with results presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.³ 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 V600positive disease who had received a BRAF inhibitor with or without a MEK inhibitor.⁴

The 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 stable disease 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.

“One-third of patients had a response [to lifileucel], and of the patients who had a response, half of them were alive at the 4-year follow-up. There is margin to improve on that, but it’s exciting. It’s a treatment for those patients who don’t have any other effective treatments available,” Mushtaq said.

Study Design

The study evaluated lifileucel in patients 18 years and older 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

The primary end point was ORR; secondary end points included DOR, disease control rate, PFS, OS, and safety.

Patient Characteristics

At the data cutoff date of November 20, 2024, the median follow-up was 57.8 months. 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.³

“Overall, these findings suggest that TIL therapy offers a promising option for patients with solid tumors,” Mushtaq said. "In addition, TIL therapy is undergoing evaluation in melanoma in the first-line setting,” he concluded.

REFERENCES 1. Mushtaq MU. Tumor-infiltrating lymphocytes (TIL) therapy in metastatic melanoma. Presented at: 2025 National Immune Cell Effector Therapy (ICE-T) Conference; July 26 2025; Orlando, FL. 2. Mushtaq MU, Abdelhakim H, Selby L, et al. Reduced dose f ludarabine and cyclophosphamide lymphodepletion before tumor-infiltrating lymphocyte therapy in melanoma. Future Oncol. 2025;21(13):1631-1637. doi:10.1080/14796694.2025.2498842 3. Medina T, Chesney JA, Kluger HM, et al; C-144-01 Investigators. Long-term efficacy and safety of lifileucel tumor-inf iltrating lymphocyte (TIL) cell therapy in patients with advanced melanoma: a 5-year analysis of the C-144-01 study. J Clin Oncol. Published online June 2, 2025. doi:10.1200/ JCO-25-00765 4. 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