All about Acral Melanomas: Summary of Current Knowledge and Forward Thinking Therapies

Original Article: Acral melanoma: clinical advances and hope for the future

What are the key takeaways of this article?

Acral melanomas, a rare subtype of melanoma, are understudied in modern day trials. Acral lentiginous melanoma (ALM) specifically have distinct histologic and molecular features, including a lack of ultraviolet-related mutational signatures. Although the incidence of ALM is similar across patients of different racial and ethnic backgrounds, it is the most common form of melanoma in patients of African, Asian and Latin American descent.

At present, advances in treatment approaches are typically derived from retrospective analyses or extrapolated from data based on non-acral cutaneous melanoma. This study by Perez et al., 2023 summarizes the current literature on ALMs as well as modern-day systemic immune and targeted therapies.

Currently, complete surgical excision is the gold standard of care for early-stage, localized melanoma and for the diagnosis of acral surface melanomas. Unfortunately, the acral surface poses a technical challenge due to limited laxity in the area. Additionally, the guidelines for sentinel lymph node biopsy in patients with ALM are largely extrapolated from studies that include only a small proportion of patients with this subtype. Yet, in one study, it was found that the ALM subtype was independently associated with the highest risk of sentinel lymph node positivity.

Immune check inhibitors anti-programmed death (PD-1) agents are promising second-line therapies for ALM. Firstly, a tumor response rate of 15.8% was found for pembrolizumab as part of the KEYNOTE-151 trial. Secondly, a similar survival outcome between both ALM and non-acral cutaneous melanomas was found using nivolumab in the CheckMate 172 trial. Lastly, nivolumab in combination with the lymphocyte activation gene 3 (LAG-3) inhibitor relatlimab showed improved progression free survival (PFS) for acral melanoma, both untreated metastatic or unresectable. By contrast, there was no statistically significant improved overall survival rates in a large multicenter retrospective analysis of 325 patients with unresectable stages III and IV ALM who were treated with a combination of anti–PD-1 therapy and ipilimumab vs ipilimumab or anti–PD-1 therapy. This reaffirms the need for further research including a variety of melanoma stages.

Targeted molecular therapy was also reviewed as a growing novel approach to acral melanomas but there is minimal and conflicting evidence surrounding BRAF targeted therapy. Compared to non-acral cutaneous melanomas, mutations in BRAF V600E are considerably less common in acral melanoma but BRAF V600E–mutant acral melanoma lack the characteristic gene amplifications seen in ALM. One retrospective analysis of 27 patients with BRAF V600E–mutated metastatic melanoma treated with BRAF-targeted therapy resulted in an objective response rate (ORR) of 78.9%, consistent with randomized controlled trials for patients with cutaneous melanoma. Conversely, another retrospective analysis of 21 patients with BRAF V600E–mutated ALM treated with BRAF-targeted therapy reported an ORR of only 38.1%.

In contrast to adjuvant therapy, neoadjuvant treatment of melanoma allows for monitoring of in vivo tumor response to treatment. This is particularly appealing for ALM, where treatment response is less certain. The use of apatinib and camrelizumab in the neoadjuvant setting for ALM is under investigation with some promising evidence for pembrolizumab in the SWOG S1801 trial.

The role of regional therapies (intralesional and intra arterial) for advanced ALM is also not well studied. Despite this, the recurrence patterns on distal extremities makes regional approaches suited for recurrent disease. One case report by Franke and colleagues outlined a patient with primary ALM who achieved a complete response with intralesional talimogene laherparepvec (T-VEC) therapy, which was previously approved in the OPTiM trial for other histological subtypes. Further studies evaluating the efficacy of combining intralesional and systemic therapies will be required before this combination can be routinely considered.

Publication Date: December 10th, 2023

Reference: Perez, M. C., Messina, J. L., Karapetyan, L., Neves, R. I., & Sondak, V. K. (2023). Acral melanoma: clinical advances and hope for the future. Clinical advances in hematology & oncology : H&O, 21(8), 400–409.

Summary By: Jaycie Dalson