Standardized guidelines for acral and nail unit melanoma treatment are lacking

To the Editor: We appreciate Skudalski et al’s1Skudalski L. Waldman R. Kerr P.E. et al.Melanoma: an update on systemic therapies.J Am Acad Dermatol. 2022; 86: 515-524Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar review of therapies for unresectable stage III, stage IV, or recurrent melanomas. Programmed cell death protein-1 (PD-1) inhibitor monotherapy, or in combination with lymphocyte activation gene-3 inhibitor (relatlimab) or cytotoxic T-lymphocyte associated antigen 4 inhibitor (ipilimumab), is the standard of care. In this letter, we focus specifically on advanced acral melanoma (AM) and nail unit melanoma (NUM) treatment. AM/NUM is a histopathological subtype of cutaneous melanoma (CM) with distinct epidemiologic and molecular features, including lower tumor mutational burden, higher genomic structural alteration rates, and lack of association with UV radiation.2Farshidfar F. Rhrissorrakrai K. Levovitz C. et al.Integrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11. 21 to metastasis.Nat Commun. 2022; 13: 1-16PubMed Google Scholar Historically, AM/NUM have had worse clinical outcomes versus other CMs. For example, in an analysis of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program, 1986-2005,3Bradford P.T. Goldstein A.M. McMaster M.L. et al.Acral lentiginous melanoma: incidence and survival patterns in the United States, 1986-2005.Arch Dermatol. 2009; 145: 427-434Crossref PubMed Scopus (374) Google Scholar the 5- and 10-year overall survival of 1413 patients with acral lentiginous melanoma (80.3% and 67.5%, respectively) was lower than that of 88,886 patients with CM (91.3% and 87.5%, respectively) (P < .001, both). However, the development of targeted and immune therapies has dramatically altered the landscape of melanoma treatment, with 5-year median survival improving from <10% to >50% over the past decade.4Wolchok J.D. Chiarion-Sileni V. Gonzalez R. et al.Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma.J Clin Oncol. 2022; 40: 127-137Crossref PubMed Scopus (170) Google Scholar Although AM/NUM patients are candidates for these newer systemic agents, less is known about their efficacy in AM/NUM; few prospective studies in patients with AM/NUM have been conducted, and clinicians must consider retrospective data for patient management. The most pressing clinical question in advanced melanoma is which patients benefit more from combination immunotherapy versus anti–PD-1 monotherapy. While this is formally unknown for AM/NUM, retrospective subgroup analyses from large clinical trials such as the Relativity-047 study suggested relatlimab + nivolumab has a higher response rate but similar progression-free and overall survival for patients with AM compared to nivolumab alone.5Tawbi H.A. Hodi F.S. Lipson E.J. et al.Nivolumab (NIVO)+ relatlimab (RELA) versus NIVO in previously untreated metastatic or unresectable melanoma: OS and ORR by key subgroups from RELATIVITY-047.J Clin Oncol. 2022; 40: 9505https://doi.org/10.1200/JCO.2022.40.16_suppl.9505Crossref Google Scholar However, the limited number of patients and resultant overlapping confidence intervals make the possible increased benefit for this combination, and other combinations such as nivolumab + ipilimumab, unclear. Dermatologists and oncologists must consider individual patient characteristics and performance status when determining treatment regimens and weigh risk-benefit profiles of using anti–PD-1 therapies in combination with other agents. Due to the relative rarity of AM/NUM, execution of large, controlled, randomized, phase-III clinical trials in these patients is difficult. Single-arm studies may be more practical. At minimum, despite distinct biology, patients with AM/NUM should be included in clinical trials of novel agents, and separate subgroup analyses should continue to highlight efficacy within AM/NUM patients. We thank Skudalski et al1Skudalski L. Waldman R. Kerr P.E. et al.Melanoma: an update on systemic therapies.J Am Acad Dermatol. 2022; 86: 515-524Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar for their thorough review of advanced melanoma treatment. We have discussed treatment for AM/NUM patients, particularly since the current survival and response rates of AM/NUM versus other CMs are less well described and because there are limited clinical trials available specifically for this population. As a result, standardized treatment guidelines for AM/NUM patients are lacking. Specifically, whether patients with AM/NUM benefit more greatly from combination immunotherapy versus anti–PD-1 monotherapy remains unclear. Future trials should prioritize AM/NUM arms and ensure dedicated subgroup analyses to help refine standardized treatment guidelines for this understudied patient population. Ms Falotico has no conflicts of interest. Dr Postow serves as a consultant for BMS, Merck, Array BioPharma, Novartis, Incyte, NewLink Genetics, Aduro, Eisai, and Pfizer and receives institutional support from RGenix, Infinity, BMS, Merck, Array BioPharma, Novartis, and AstraZeneca. Dr Lipner has served as a consultant for Ortho Dermatologics, Verrica, Hoth Therapeutics, BelleTorus Corporation, and Hexima.