Lifileucel Offers Promising Long-Term Efficacy in Advanced Melanoma

Patients with advanced melanoma have limited treatment options after progression on immune checkpoint inhibitors. Adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) is now an approved option that has shown efficacy, as discussed by Barbara T. Ma, MD, MS, assistant professor of medicine at Weill Cornell Medicine and assistant attending physician at New York Presbyterian Hospital, in a recent in-person Community Case Forum meeting in New York City. Although the treatment requires hospitalization for lymphodepleting chemotherapy and associated short-term toxicities, the trial data presented by Ma showed responses that deepened over time with lifileucel (Amtagvi) TIL therapy.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

Targeted Oncology: What was the design and patient population of the C-144-01 trial (NCT02360579) of lifileucel?

Barbara Ma, MD: This was a phase 2 registrational trial where they looked at patients with unresectable or metastatic melanoma. They had been treated with more than 1 prior systemic therapy, including anti–PD-1, and if BRAF mutated, they [must have had progression] already on a BRAF-MEK inhibitor. They had different cohorts, but essentially it was cohorts 2 and 4 [which used cryopreserved TILs] that we're focused on. They used the eligibility criteria of excellent performance status. They didn't have a limit on the number of prior therapies. Patients had a harvestable site greater than 1.5 cm, and they had at least 1 target tumor lesion that they could use to track for response assessment. In the registrational trial, it took 3 weeks to generate the lifileucel TIL, and all patients received lymphodepleting chemotherapy, the lifleucel infusion, and then up to 6 doses of high-dose interleukin [IL]-2.

Essentially, they had good performance status. They had some patients with mucosal and acral melanoma, but the majority were patients with cutaneous melanoma. About one-quarter of them were BRAF mutated. In terms of the baseline lesions and the median target lesion, they were in the range of more than 9 cm. Looking at lactate dehydrogenase is how we can get a sense of how fast the turnover is. We use it as a soft biomarker in melanoma. One point to note is that the median number of prior therapies was 3, essential what we consider heavily pretreated, because most of these patients have already gone through the best options that could have been available.¹

What were the efficacy outcomes for lifileucel?

The overall objective response rate was 31.4%.¹ We're looking at 12% for nivolumab/relatlimab [Opdualag] after ipilimumab [Yervoy] plus nivolumab [Opdivo],² or 11% to 15% for chemotherapy…. Chemotherapy doesn't have a durable effect either. The majority here did have [at least] stable disease [SD]. There were some complete responses [CRs], there were partial responses [PRs], but the response rate of 31.4% is a nice signal. The 12-month PFS rate was 28.3%; the confidence interval was 20.8% to 36.3%, and in the 5-year analysis that was presented at the 2025 American Society of Clinical Oncology Annual Meeting, the 5-year overall survival [OS] rate was 19.7%.³ That's 20% of patients at the 5-year follow-up who received the infusion 5 years ago, and they're being observed off treatment and the median OS follow up was 57.8 months. But the key point is that they can still have a durable response. That is what I thought was a pretty exciting signal and I thought that does cement lifileucel as a standard-of-care option, especially in the second-line setting.

All of those patients who either have SD or PR over time can continue to have deepening responses, so even if it’s not a CR right off the bat, if you follow patients for long enough and you scan them many times, their responses become deeper as you go out, and it can turn into a CR. Even when they were more than a year out, they went from a PR to CR, and that's an even more impressive signal, the fact that you could even get a chance at seeing that deepening response. Duration of response is a pretty flat curve. [With a median of] 36.5 months, it's still long lasting.³ The percent of patients with sum of diameters reduction was 79.3%, but I think it is a very striking point where you can still see the responses deepen over time, even more than a year out.

What was the safety profile of this regimen?

[In terms of] adverse events in the patients receiving lifileucel, the majority is thrombocytopenia [grade 3/4 in 76.8%].¹ But remember, they get the TIL and the IL-2 essentially a week after the lymphodepleting chemotherapy. A lot of this is probably more from the chemotherapy they've received. They get TIL and they get IL-2 and spike a fever, but they're neutropenic, so that's why we see febrile neutropenia [in 41.7%], but it seems like that's the bulk of the toxicities that they see. When looking at the adverse events over time from the lifileucel infusion, the majority is in those first 2 weeks, so that's why you see a spike then, and it’s that immediate setting from lymphodepleting chemotherapy and the IL-2. Now, [in terms of] how long the cytopenias last, count recovery does happen, but again, the bulk of the toxicities are early.

What is the recovery like for patients who receive lifileucel?

The bulk of the toxicity is in the first 14 days because of recovering from the toxicities of the chemotherapy they get and the IL-2, so they don't get discharged from the hospital until their [blood cell] counts recover. Usually that takes a week after the TIL, so that's why I say that average hospitalizations are 2 and a half to 3 weeks. We do weekly follow-ups in that first month post TIL, and in my clinic, I've seen the bulk of them feel a lot better because they've had a chance to recover at home. It can be a life-changing shot when we see those responses, [although] not every patient will respond.

In my own clinic I’ve had the not-ideal patient who I will do my best to get them through, but as long as they're for it, there are ways for us to try to reduce the toxicity from the chemotherapy. Even in terms of IL-2, do we need all the doses of IL-2? The TIL working group says you don't need all the doses of IL-2,⁴ but in order to know that you have to know the dose of the lifileucel TIL you're giving, because I do think that there's probably some dose-dependent effects. But other centers have seen responses even with 0 doses of IL-2. But in terms of recovery, usually the bulk is in the beginning.

DISCLOSURES: There are no known relevant disclosures.

REFERENCES:

1. Chesney J, Lewis KD, Kluger H, et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. J Immunother Cancer. 2022;10(12):e005755. doi:10.1136/jitc-2022-005755

2. Medina T, Chesney JA, Kluger HM, et al. Lifileucel in patients with advanced melanoma: 5-year outcomes of the C-144-01 study. J Clin Oncol. 2025;43(suppl 16):9515. doi:10.1200/JCO.2025.43.16_suppl.9515

3. Ascierto PA, Lipson EJ, Dummer R, et al. Nivolumab and relatlimab in patients with advanced melanoma that had progressed on anti-programmed death-1/programmed death ligand 1 therapy: results from the phase I/IIa RELATIVITY-020 trial. J Clin Oncol. 2023;41(15):2724-2735. doi:10.1200/JCO.22.02072

4. Buchbinder E, Lotze MT, Margolin KA, et al. Role of high-dose interleukin-2 for melanoma in the age of cellular therapy. J Immunother Cancer. 2025;13(5):e011119. Published 2025 May 30. doi:10.1136/jitc-2024-011119