Top 5 Takeaways on Advances in Rare Melanoma Management

Rare melanomas—including acral, mucosal, and uveal subtypes—present distinct biological and clinical challenges compared with cutaneous melanoma. While they account for a small percentage of total melanoma cases, their unique genetic profiles and historical resistance to standard therapies necessitate specialized management strategies. At the 22nd Annual International Symposium on Melanoma and Other Cutaneous Malignancies, Mark B. Faries, MD, FACS, a surgical oncologist specializing in cutaneous oncology from Cedars-Sinai Medical Center, provided an update on emerging treatments and clinical trial data that are redefining the standard of care for these rare malignancies.¹

1. Neoadjuvant PD-1 Blockade Shows High Efficacy in Desmoplastic Melanoma

Desmoplastic melanoma (DM), though rare, demonstrated significant sensitivity to immunotherapy.² Results from the phase 2 SWOG S1512 trial (NCT02775851) showed that 3 cycles of neoadjuvant pembrolizumab (Keytruda) achieved a pathologic complete response (pCR) in 71% of patients with resectable DM. Long-term data for both resectable and unresectable cohorts reported only two melanoma-related deaths among 55 patients, highlighting the robust efficacy of anti–PD-1 therapy in this subtype.

2. Targeted Therapy for KIT-Mutated Subtypes Remains a Relevant Option

KIT mutations are more prevalent in acral and mucosal melanomas than in cutaneous types.³ A meta-analysis of 19 studies involving KIT inhibitors such as imatinib (Gleevec), nilotinib (Tasigna), and dasatinib (Sprycel) showed a pooled objective response rate (ORR) of 15%. Nilotinib demonstrated a slightly higher ORR of 20%, while sub-analysis by site showed an ORR of 22% for acral and 14% for mucosal melanomas.

3. Immunotherapy Response Rates Differ Across Rare Subtypes

Although immune checkpoint inhibitors (ICI) are standard, their efficacy varies significantly between rare subtypes and cutaneous melanoma.

• Acral Melanoma: Dutch cohort data revealed lower ORRs for acral vs cutaneous melanoma with both PD-1 monotherapy (34% vs 54%) and ipilimumab (Yervoy)/nivolumab (Opdivo; 33% vs 53%).⁴
• Mucosal Melanoma: Pooled data for nivolumab/ipilimumab combination therapy showed a 37.1% (95% CI, 21.5%-55.1%) ORR in mucosal cases compared with 60.4% (95% CI, 54.9%-65.8%) in cutaneous cases.⁵

4. Uveal Melanoma: Tebentafusp and Emerging Cellular Therapies

Uveal melanoma is biologically distinct, often driven by GNAQ or GNA11 mutations. Tebentafusp-tebn (Kimmtrak) remains a cornerstone for patients who have HLA-A*02:01-positive status. In the phase 3 IMCgp100-202 trial (NCT03070392), the median overall survival was 22 months with tebentafusp vs 16 months for pembrolizumab/ipilimumab/dacarbazine.⁶ Beyond tebentafusp, PRAME-specific T-cells (IMA203) are showing promise, with a 67% ORR in a phase 1 trial (NCT03686124) of 16 patients.⁷

5. Neoadjuvant Strategies are Expanding to Mucosal Melanoma

Recent studies have evaluated neoadjuvant ICI for node-positive or satellite mucosal melanoma.⁸ In a study of 36 patients treated primarily with combination ipilimumab/nivolumab, the major pathologic response (MPR) rate was 26%, suggesting a potential role for earlier systemic intervention in this aggressive subtype.

References

1. Faries M. Latest advances in managing rare melanomas. Presented at the 22nd Annual International Symposium on Melanoma and Other Cutaneous Malignancies; Beverly Hills, CA; February 21, 2026.
2. Kendra KL, Bellasea SL, Eroglu Z, et al. Anti-PD-1 therapy in unresectable desmoplastic melanoma: the phase 2 SWOG S1512 trial. Nat Med. 2025;31(11):3668-3674. doi:10.1038/s41591-025-03875-5
3. Steeb T, Wessely A, Petzold A, et al. c-Kit inhibitors for unresectable or metastatic mucosal, acral or chronically sun-damaged melanoma: a systematic review and one-arm meta-analysis. Eur J Cancer. 2021;157:348-357. doi:10.1016/j.ejca.2021.08.015
4. van Not OJ, de Meza MM, van den Eertwegh AJM, et al. Response to immune checkpoint inhibitors in acral melanoma: A nationwide cohort study. Eur J Cancer. 2022;167:70-80. doi:10.1016/j.ejca.2022.02.026
5. D'Angelo SP, Larkin J, Sosman JA, et al. Efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: a pooled analysis. J Clin Oncol. 2017;35(2):226-235. doi:10.1200/JCO.2016.67.9258
6. Nathan P, Hassel JC, Rutkowski P, et al. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2021;385(13):1196-1206. doi:10.1056/NEJMoa2103485
7. Patel SP, Tsimberidou AM, Luke JJ, et al. Efficacy and safety of IMA203, a PRAME-directed T-cell receptor (TCR) T-cell therapy, in patients with previously treated advanced or metastatic uveal melanoma from a phase I trial. Ann Oncol. 2025;36(suppl 2):S882. doi:10.1016/j.annonc.2025.08.2228
8. Ho J, Mattei J, Tetzlaff M, et al. Neoadjuvant checkpoint inhibitor immunotherapy for resectable mucosal melanoma. Front Oncol. 2022;12:1001150. doi:10.3389/fonc.2022.1001150