How Patient Factors Steer Treatment Selection in Metastatic Melanoma

After progression on anti–PD-1 therapy for advanced melanoma, emerging options include tumor-infiltrating lymphocyte (TIL) therapy with lifileucel (Amtagvi) and the newly approved oncolytic virus vusolimogene oderparepvec-wtpg (RP1; Tudriqev) combined with nivolumab (Opdivo), each chosen according to tumor location, mutation status, and tolerance of earlier treatment.

During a live Case-Based Roundtable event in Denver, Colorado, Theresa Medina, MD, associate professor at the University of Colorado Anschutz, reviewed first-line and second-line treatment data and moderated discussion of a 51-year-old woman with BRAF V600E-mutated melanoma and a 64-year-old man with mucosal melanoma, both with progression after checkpoint inhibitor therapy. Medina noted that prospective comparisons between regimens are lacking and that selection depends on disease features and the patient’s tolerance of treatment.

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This article is part 1 of a 2-part series from a Case-Based Roundtable event.

CASE SUMMARY 1

• A 51-year-old woman diagnosed 2 years ago with pT2aN1a BRAF V600E-mutated cutaneous melanoma of the left upper back for which she underwent wide excision and sentinel lymph node biopsy (SLNB) – declined adjuvant therapy
• Five months after diagnosis, developed pulmonary and hepatic metastases
• Brain MRI negative for central nervous system (CNS) involvement
• First-line: nivolumab + ipilimumab (Yervoy)
  • Patient achieved a partial response, lasting about 11 months
  • No adverse events of note
  • Progression with new liver lesions
• Second-line: dabrafenib (Tafinlar) + trametinib (Mekinist)
  • Achieved disease control for 8 months
  • Progression noted with new bone lesions and growth of existing liver lesions
  • Toxicities included intermittent but severe fevers and fatigue
• Presents today with fatigue and moderate right-sided rib pain
• Eastern Cooperative Oncology Group performance status (ECOG PS) of 1
• Brain MRI negative for CNS involvement

EVENT RECAP

For the first patient, 6 of 7 respondents (85.7%) said they were most likely to recommend lifileucel and 1 chose nivolumab plus relatlimab-rmbw (Opdualag); no one chose chemotherapy or talimogene laherparepvec (T-VEC; Imlygic), which Medina said would not suit a patient with visceral disease. The distribution was unchanged after the data review.

Medina analyzed the 10-year analysis of the CheckMate 067 trial (NCT01844505), in which nivolumab plus ipilimumab was associated with a median overall survival (OS) of 71.9 months and an objective response rate (ORR) of 58.3%, but 62.6% of patients had grade 3 or 4 treatment-related adverse events (TRAEs) and 44.7% stopped treatment because of them.¹

In the 4-year update of the RELATIVITY-047 trial (NCT03470922), median OS was numerically longer with nivolumab plus relatlimab than with nivolumab alone, at 53.3 months vs 33.2 months (HR, 0.77), with an ORR of 43.9% vs 33.4% and grade 3 or 4 TRAEs in 22.3% vs 12.0%; these were descriptive comparisons.² The trials enrolled different populations, so the results cannot be compared directly.

Medina considers either combination reasonable for an appropriate patient and described a preference, though she said she often leans toward ipilimumab plus nivolumab. She said ipilimumab plus nivolumab is more active in CNS disease and she favors it for liver and bone metastases, and reserves nivolumab plus relatlimab for patients who are frail or have autoimmune disease.

For patients with disease progression during adjuvant therapy, Medina tends to choose ipilimumab plus nivolumab because the disease biology is probably worse and noted that no efficacy data exist for immunotherapy after adjuvant treatment. Sam Shelanski, MD, of Banner MD Anderson in Longmont, Colorado, described a patient with progression 5 months into adjuvant nivolumab and was hospitalized with adrenal insufficiency after the first dose of ipilimumab plus nivolumab, and he considered moving them to the TIL pathway early.

For patients with BRAF V600 mutations, Medina said the evidence supports starting with immunotherapy. In the 5-year analysis of the DREAMseq trial (NCT02224781), the OS rate was 63.3% for patients who started with ipilimumab plus nivolumab and 33.9% for those who started with dabrafenib plus trametinib.³ If targeted therapy is used, Medina said a BRAF inhibitor should be paired with a MEK inhibitor and prefers encorafenib (Braftovi) plus binimetinib (Mektovi) for its tolerability and easier dose reductions.

Lifileucel was the first agent to receive an FDA indication in the second-line setting post–PD-1, Medina said. In the 5-year analysis of the C-144-01 trial (NCT02360579), a single-arm study of 153 patients, the ORR was 31.4% (5.9% complete and 25.5% partial responses), median duration of response (DOR) was 36.5 months, median OS was 13.9 months, and the 5-year OS rate was 19.7%.⁴ “I think of this as how ipilimumab looked when it was first approved,” Medina said. Shelanski, who treated patients before checkpoint inhibitors, noted that the response rate in a heavily pretreated population looked good in this setting.

A retrospective analysis of 43 patients given commercial lifileucel reported an ORR of 44% (n = 18); the response rate was 52% in patients with 2 or fewer prior lines of therapy and 33% in those with more than 2, a descriptive comparison in small subgroups.⁵ Responders made up 39% of patients with BRAF V600 mutations and 48% of those without, and Medina suggested that progression on targeted therapy may leave tumors more resistant to immune-based treatment.

CASE SUMMARY 2

• A 64-year-old man with unresectable stage IV mucosal melanoma presents today for a follow-up visit.
• Primary tumor on right maxilla
• Multiple nodal lesions and lung lesions
• Genetic testing revealed BRAF wild-type, KIT wild-type
• Current therapy: nivolumab + ipilimumab → nivolumab maintenance
  • Patient achieved a partial response with no residual toxicity
• PET scan shows increase in size and number of lung lesions
• Brain MRI negative for metastases
• ECOG PS of 0
• Normal lactate dehydrogenase (levels

For the second patient, 6 of 7 respondents (85.7%) chose lifileucel and 1 chose rechallenge with ipilimumab plus nivolumab. Medina would consider lifileucel for mucosal melanoma, noting that platinum-based chemotherapy can also produce responses. In a 12-patient mucosal melanoma subgroup of C-144-01, 1 patient had a complete response and 5 had partial responses.⁶

The FDA granted accelerated approval to vusolimogene oderparepvec with nivolumab on August 6, 2026, for adults with unresectable advanced cutaneous melanoma that progressed on a regimen based on a PD-1–blocking antibody. The label reports an ORR of 24.2% (95% CI, 15.8%-34.3%) and a median DOR of 14.1 months among 91 efficacy-evaluable patients with at least 1 noninjected lesion. In all 140 patients in the single-arm IGNYTE trial (NCT03767348), the ORR was 33.6% and the median DOR was 24.8 months, and the median OS was 32.2 months (95% CI, 25.8-39.2), with a 3-year OS rate of 45.5% (95% CI, 35.8%-54.7%).⁷ Medina said the FDA’s feedback was that the trial did not adequately show the contribution of the virus beyond nivolumab, and that the randomized IGNYTE-3 trial (NCT06264180) compares the regimen with physician’s choice, which does not include lifileucel. These populations differed, so the results cannot be compared directly.

Between the 2 approved options, Medina said, response durability may favor lifileucel, but some patients are not fit for cell therapy. Vusolimogene oderparepvec can also be injected into deep and visceral lesions, not only cutaneous and nodal ones.

Medina discussed the choice between lifileucel and vusolimogene oderparepvec as a trade-off between durability of response and a patient’s ability to undergo cell therapy. Without a randomized trial comparison between the 2 newer options, selection continues to rest on fitness, tumor location, and prior therapy.

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_{DISCLOSURES: Medina previously reported institutional research funding from Merck, Replimune, Bristol Myers Squibb, Iovance Biotherapeutics, Pfizer, Genentech, Moderna Therapeutics, TriSalus Life Sciences, Regeneron, Immatics.}

REFERENCES

1. Wolchok JD, Chiarion-Sileni V, Rutkowski P, et al. Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma. N Engl J Med. 2025;392(1):11-22. doi:10.1056/NEJMoa2407417

2. Lipson EJ, Stephen Hodi F, Tawbi H, et al. Nivolumab plus relatlimab in advanced melanoma: RELATIVITY-047 4-year update. Eur J Cancer. 2025;225:115547. doi:10.1016/j.ejca.2025.115547

3. Atkins MB, Lee SJ, Chmielowski B, et al. DREAMseq: A phase III trial of treatment sequences in BRAFV600-mutant (m) metastatic melanoma (MM)—Final clinical results. J Clin Oncol. 2025;43(suppl 16):9506. doi:10.1200/JCO.2025.43.16_suppl.9506

4. Medina T, Chesney JA, Kluger HM, et al. Long-term efficacy and safety of lifileucel tumor-infiltrating lymphocyte cell therapy in patients with advanced melanoma: a 5-Year analysis of the C-144-01 Study. J Clin Oncol. 2025;43(33):3565-3572. doi:10.1200/JCO-25-00765

5. Karapetyan L, Moser J, Ma BT, et al. Real-world, evidence-based, retrospective study of patients infused with commercially released lifileucel for unresectable or metastatic melanoma. Presented at: 2026 Transplantation & Cellular Therapy Meetings. February 4-7, 2026. Salt Lake City, Utah. Abstract 48.

6. Kluger H, Grigoleit GU, Thomas S, et al. Lifileucel tumor-infiltrating lymphocyte cell therapy in patients with unresectable or metastatic mucosal melanoma after disease progression on immune checkpoint inhibitors. Cancer Commun (Lond). 2025;45(10):1229-1234. doi:10.1002/cac2.70050

7. . Wong MKK, Sacco JJ, In GK, et al. A 3-year landmark overall survival analysis of RP1 plus nivolumab in patients with anti-PD-1-failed melanoma from the IGNYTE clinical trial. J Clin Oncol. 2026;44(16 suppl):9518. doi:10.1200/JCO.2026.44.16_suppl.9518