Considering Lifileucel for PD-1–Refractory Advanced Melanoma

Metastatic melanoma is challenging for patients who experience disease progression on initial immune checkpoint inhibitor and targeted therapies. During a live event in Nashville, Tennessee, Dr. Michael C. Lowe, MD, MA, an associate professor in the Division of Surgical Oncology at Emory University School of Medicine and co-chair of the Melanoma Working Group at Winship Cancer Institute of Emory University, discussed treatment based on the case of a patient with metastatic melanoma who needed later-line treatment. Lowe detailed the efficacy of lifileucel (Amtagvi), a tumor-infiltrating lymphocyte (TIL) therapy, for patients with similar diagnoses.

Register today to join a Case-Based Roundtable near you.

CASE SUMMARY

• A 51-year-old woman was diagnosed 4 years ago with cutaneous melanoma of the left upper back.
• ECOG performance status: 1
• Lactate dehydrogenase (LDH) elevated 2 times upper limit of normal
• BRAF V600E-positive mutation detected at diagnosis
• Developed pulmonary and hepatic metastases within 12 months
  despite excision
• Brain MRI negative for central nervous system involvement
• First-line: nivolumab (Opdivo) plus ipilimumab (Yervoy)
  • Patient achieved a partial response, lasting about 11 months
  • Progression with new liver lesions
• Second-line: dabrafenib (Tafinlar) plus trametinib (Mekinist)
  • Achieved disease control for 8 months
  • Progression noted with new bone lesions and growth of existing liver lesions
  • Toxicities included intermittent fevers and fatigue
• Presented today with fatigue, mild right-sided rib pain, and weight loss of about 10 lb over the last 3 months

Targeted Oncology: What are the data behind choosing lifileucel for this patient with metastatic melanoma?

Michael C. Lowe, MD, MA: What informs the idea that TIL [is a] popular answer for PD-1–refractory patients is based on a phase 2 clinical trial [C-144-01; NCT02360579]. This is a phenomenal data set when it comes to pooling resources to get a hard therapy through a hard trial, to give us some good data.¹

The trial enrolled patients with unresectable metastatic melanoma who had at least 1 prior line of therapy that had to have the anti–PD-1 therapy backbone. They could or could not have had a BRAF [mutation], but if they did, they had to have had therapy for it.

The 2 cohorts that matter in this discussion are cohorts 2 and 4. Cohort 2, at least for the purposes of this publication, were the historical patients that they had already reported, then they kept running the trial for an additional 75 patients who they call cohort 4. The study population is cohorts 2 plus 4, so [I'll discuss] data from both sets, but what I want you to think about is the combination of those cohorts.

What were the end points and baseline characteristics of the C-144-01 trial?

The primary end point was objective response rate [ORR], with appropriate secondary end points. Patients had to have at least 1 tumor resectable and 1 tumor that could be followed. They had good performance status, and there was no limit on number of prior therapies. I think one of the patients had 10 or 11 prior therapies, so this was a broad patient population. They received a non-myeloablative lymphodepletion, lifileucel therapy, and IL-2 to follow.

For the combination of cohorts 2 and 4, importantly, most patients had ECOG performance status of 0. Most patients had cutaneous disease, although there were a few patients with mucosal disease in there. The largest lesion diameter was a median of almost 10 cm, so this is a pretty high burden of disease patient population. The median number of previous lines of therapy was 3. There were patients with a high LDH percentage. This was a difficult-to-treat patient population.

How did this patient population do with lifileucel in terms of response and survival?

The take home point is the ORR of 31.4%. This is complete and partial responses, 8 patients with complete response, 40 patients with a partial response, and then an additional 71 patients with stable disease, which is—without RP1 or clinical trial—a home run for a patient with PD-1–refractory disease. There were 46% of patients maintaining stable disease.

There was a relatively short progression-free survival [PFS; median, 4.1 months]. We've seen that with other systemic therapies…[but] the progression-free survival is not always the story. Then there was a 12-month PFS rate of 28.3%.

Overall survival [OS] for this patient population was longer than the historic OS of the entire metastatic population, which I think is a win. It was almost 14 months of median OS, with a 5-year OS rate of 19.7%.²

The duration of response was quite impressive. The patients who get a response maintain it. This is unlike dabrafenib/trametinib, and sometimes even with PD-1–based immunotherapy. Of course there was early cut-off for patients whose disease progressed rapidly, but if they maintain a durable response out past that 6- to 9-month range, most patients maintain their response as a durable one.

There were a number of patients who had a complete response some distance from their cell therapy, at 18, 21, or 33 months until they had their complete response [longest ongoing response, 58.7 months]. It's these early markers of response that we tend to hope for and say if you're not getting a response, we need to switch, we need to escalate, or we need to do something. But a good number of these patients are still having a response quite some time after their initial cell therapy.

What was the toxicity profile for these patients in the C-144-01 trial?

There was 100% toxicity in these patients, a majority of them hematologic because of the chemotherapy or the IL-2.¹ They were all manageable and all relatively short after the institution of the therapies. For the timing of the adverse events, the highest rate of adverse events of all grades was right at the time of the initiation of lymphodepletion the cell therapy and the IL-2 with very few long-term toxicities. The onset of toxicities rarely happens beyond the initial therapy.

Register today to join a Case-Based Roundtable near you.

_{DISCLOSURES: Lowe previously reported being a consultant for and receiving research funding from Merck and Bristol Myers Squibb.}

_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(16_suppl):9515-9515. doi:10.1200/jco.2025.43.16_suppl.9515}