Adjuvant treatment in advanced melanoma: How far have we come?

Melanoma is the 5th most common cancer in both males and females in Europe and the United States and remains the most serious form of skin cancer. Approximately 325,000 people worldwide are diagnosed by melanoma every year. In Europe, both the incidence and mortality of melanoma are increasing, although these trends vary significantly between different European populations. Mortality rates are notably stabilizing or even declining in certain regions and age groups.1, 2 In the United States, mortality rates have declined by approximately 2% per year from 2016 to 2020. A major contributor to this epidemiological trend has been the introduction of effective new treatments for advanced melanomas, such as immune checkpoint blockers (ICB) and BRAF-MEK inhibitors.3 According to the National Cancer Institute, the number of people living with metastatic melanoma increased by 258% between 1990 and 2018.4 Over the past decade, the relative survival rate for patients diagnosed with advanced stage melanoma has doubled from 20.6% to 39.3%.5 With the approval of ICBs and targeted agents in the earlier adjuvant setting, patients with high risk melanoma benefit from a significant improvement in recurrence free survival (RFS). However, the decision about whether to prescribe a specific adjuvant therapy entails careful selection of patient on the basis of risk of disease relapse and likelihood of therapeutic efficacy. The patient population enrolled in randomized controlled trials is stringently selected and may not represent the heterogeneous population of patients that physicians will evaluate and treat on a daily basis in their clinical practice. The study presented by Schumann K6 and colleagues in this issue of JEADV offers an important contribution in this regard providing new insights into the characteristics and treatment outcomes of high risk melanoma patients receiving adjuvant systemic treatment. Their study included real world data of 1198 patients from 39 skin cancer centres in Germany, Austria and Switzerland receiving adjuvant treatment with either ICBs or combination of Dabrafenib and Trametinib (D + T). In terms of 12-month RFS, nivolumab, pembrolizumab and D + T were found to provide 72.1%, 78% and 86.5% RFS rates, respectively. These findings suggest that regardless of inclusion and exclusion criteria used in clinical trials, early treatment efficacy seen in pivotal clinical phase III studies can also be achieved in everyday practice. Furthermore, the authors reported fewer and less severe adverse events compared to data from randomized controlled trials. These results indicate that some of the toxicities reported in pivotal clinical trials may have limited clinical relevance in daily practice. Schumann and colleagues showed that both therapeutic approaches are effective with different toxicity profiles, and therefore, patients characteristics and preferences are used to guide selection of therapy. However, it should be stressed that there are no data from direct comparison trials of BRAF—MEK and ICBs. A second significant point of their analysis was that therapeutic lymph node dissection (TLND) compared with SLNB only did not improve 12 month RFS and OS in SLNB-positive patients receiving modern adjuvant treatment. These results confirm previous findings and are of great importance since the procedure of TLND carries a high risk of morbidity and lymphedema.7 However, TLND is still suggested in selected patients with clinically positive lymph nodes and lymph node recurrences. Although overall survival data are not mature, neoadjuvant ICB therapy with pembrolizumab is supported in patients with high risk node-positive melanoma and macroscopic disease that is resectable, since this approach was more effective than primary surgery followed by adjuvant immunotherapy.8 More recent data support that for patients treated with neoadjuvant immunotherapy, limited initial resection of a select involved lymph node (rather than a TLND) could be used to guide further surgery and adjuvant systemic therapy.9 In light of the final results of neoadjuvant approaches in patients with nodal metastases, we should consider the benefits of further limiting TLND in patients with nodal metastases. An important aspect of adjuvant treatment is the identification of clinical or molecular markers that can predict which patients will benefit from it. Schumann's study further confirmed the prognostic significance of immune-related adverse events (imRAEs) on disease survival whereas the development of skin toxicities from D + T (DrAE) did not affect survival rates. Although many studies support the prognostic significance of skin toxicities from ICB, more effort should put into evaluating how specific toxicities can affect survival. In a retrospective multicentre DeCOG study,10 Kahler et al showed that early macular rash within 6 weeks after therapy start was correlated to therapy outcome in patients treated with vemurafenib plus cobimetinib. In the era of skin toxicities, macular rashes have different clinical patterns and pathogenesis compared to other skin toxicities like hand-foot skin reactions or psoriasis, and their impact on survival rates needs to be assessed independently. Adjuvant therapy for melanoma has taken a major leap forward in the past 5 years. The next step for 2023 would be to develop prognostic models and personalized approaches that will enable clinicians to make the best overall informed treatment decisions. None. Data sharing not applicable