Considering Immunotherapy Rechallenge and TILs for Recurrent Mucosal Melanoma

Mucosal melanoma accounts for a small fraction of all melanoma diagnoses, but it presents with a biology that makes the second-line decision unusually complicated. Unlike cutaneous melanoma, where checkpoint inhibition has changed long-term survival expectations, mucosal subtypes are characterized by lower rates of response to PD-1 blockade and an infrequent BRAF mutation rate, removing the targeted therapy pathway that offers a meaningful alternative to many patients with cutaneous melanoma. When these patients experience disease recurrence, the standard-of-care options remain available in principle but perform considerably worse than the pivotal trial data for each drug might suggest, because those pivotal trials enrolled almost entirely cutaneous populations.

In a virtual Case-Based Roundtable event for oncologists in the Dallas-Fort Worth area, Sapna Patel, MD, the Dr William Robinson Endowed Chair in Cancer Research and director of cutaneous oncology and cell therapy for solid tumors at the University of Colorado, walked attendees through a second-line mucosal melanoma case and the data, highlighting the gaps in current evidence that should inform treatment decisions for this population.

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

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CASE SUMMARY

• A 64-year-old man with unresectable stage IV mucosal melanoma presented 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 (Opdivo) plus ipilimumab (Yervoy) → nivolumab maintenance
• The patient achieved a partial response with no residual toxicity.
• A PET scan shows an increase in size and number of lung lesions.
• Brain MRI is negative for metastases.
• ECOG performance status: 0
• Normal lactate dehydrogenase (LDH) level

EVENT RECAP

Patel observed that mucosal melanomas in North America are predominantly genitourinary in origin, making the oral maxillary primary in this case relatively uncommon, with nasal primaries more prevalent in East Asian populations.

She reviewed the landscape of immunotherapy rechallenge for patients with previously treated melanoma. In the SWOG S1616 trial (NCT03033576), the combination of nivolumab plus ipilimumab after prior anti–PD-1 therapy produced a median overall survival (OS) of 21.7 months and an objective response rate (ORR) of 28%, although the grade 3/4 toxicity rate was 56% and discontinuation due to adverse events reached 29%.¹ For nivolumab plus relatlimab-rmbw (Opdualag), the RELATIVITY-020 trial (NCT01968109) reported a median OS of 14.7 months and an ORR of 12.0% in the previously treated setting, with a substantially lower rate of high-grade adverse events.² Pembrolizumab (Keytruda) monotherapy in the second line, from KEYNOTE-002 (NCT01704287), produced an ORR of 22% to 28% depending on dose, again in predominantly cutaneous populations.³ None of these trials enrolled meaningful numbers of patients with mucosal melanoma, so Patel noted that applying these findings requires a significant interpretive leap.

The KIT wild-type result in this case also removes imatinib (Gleevec) from consideration, as KIT-mutated mucosal and acral melanomas represent a small subset where KIT inhibitors show activity, but absent a sensitizing mutation, there is no signal. Chemotherapy remains in the NCCN guidelines as a later-line option, but Patel described it as useful primarily as a bridge to another active therapy, such as tumor-infiltrating lymphocyte (TIL) therapy, rather than as a standalone treatment.⁴

Patel discussed the data on lifileucel (Amtagvi) TIL therapy in the mucosal subgroup; in the C-144-01 trial (NCT02360579), 12 patients with mucosal melanoma were enrolled across the 2 combined cohorts that formed the basis of FDA approval. Of those, 6 responded, producing a response rate numerically consistent with the overall trial ORR of 31.4%, but the 12 total were those who were treated, not necessarily those who had tumors harvested for TIL production.^5,6 “Mucosal surfaces are laden with bacteria, so the problem that often happens when you harvest a mucosal tumor is the T cells die, or the T cells become contaminated because the bacteria grow, so we haven't yet optimized how to manage that,” explained Patel.

Patel noted that this patient who has not yet exhausted all standard options, still has a good performance status, and has a normal LDH might reasonably be offered nivolumab rechallenge or nivolumab/relatlimab before moving to TIL, depending on how the treating team weighs the evidence gap.

Despite that caveat, all 10 attendees chose lifileucel. Patel commented that this was “bold,” as the lifileucel-treated cohort was small and the patient has not received immunotherapy rechallenge. “It's not wrong to say, ‘Look, we might retry [nivolumab] if they progressed on the maintenance part of [nivolumab]. It's not wrong to try [nivolumab/relatlimab]”, she said. However, the logistical delays involved in TIL therapy could justify prioritizing it earlier, considering the low success rate of immunotherapy rechallenge.

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_{DISCLOSURES: Patel previously reported advisory board, steering committee, data safety monitoring board, and consulting relationships with Bristol Myers Squibb, Cardinal Health, Castle Biosciences, Ideaya, Immatics, IO Biotech, MSD, Novartis, Obsidian, OncoSec, Pfizer, Replimune, Scancell, TriSalus Life Sciences, Veda Trials.}

REFERENCES

1. VanderWalde A, Bellasea SL, Kendra KL, et al. Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma: a randomized phase 2 trial. Nat Med. 2023;29(9):2278-2285. doi:10.1038/s41591-023-02498-y

2. 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

3. Hamid O, Puzanov I, Dummer R, et al. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017;86:37-45. doi:10.1016/j.ejca.2017.07.022

5. NCCN. Clinical Practice Guidelines in Oncology. Melanoma: cutaneous, version 2.2026. Accessed July 13, 2026. https://tinyurl.com/ycyhfyfv

5. 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

6. Medina T, Kim DW, Munhoz RR, 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