Tackling melanoma by adjuvant therapy: why, whom and how?
Authors: B. Schilling, T. Wiesner
Journal: British Journal of Dermatology (2019)

Targeted therapy with mitogen-activated protein kinase pathway inhibitiors (MAPKi, such as dabrafenib and trametinib, or vemurafenib and cobimetinib) and immune therapy with checkpoint inhibitors (ICI, such as nivolumab, pembrolizumab, or ipilimumab) have revolutionized the treatment of patients with metastatic melanoma. Although these new therapies significantly increased disease-specific survival of patients with metastasized melanoma, long-term tumour control is achieved in only a minority of patients; the majority of patients still die of metastatic disease. Targeted and immune therapies are used not only to treat patients with metastatic melanoma but are now also used in adjuvant settings. In recently published clinical trials, adjuvant targeted therapies with MAPKi and immune therapies with ICI showed promising results in patients with advanced melanoma: the Combi-AD1 trial reported a significantly lower risk of disease recurrence in patients with stage III melanoma under adjuvant therapy with the MAPKi dabrafenib and trametinib, compared with placebo. The Checkmate-2382 trial compared adjuvant therapy with nivolumab to ipilimumab, and reported a lower risk of recurrence in the nivolumab vs. the ipilimumab group. The KEYNOTE-0543 trial compared adjuvant pembrolizumab vs. placebo and also reported a significantly higher rate of patients without recurrence in the pembrolizumab group. In summary, patients with stage III1-3 or IV2 melanoma, who underwent complete resection, experienced a significantly reduced risk of disease recurrence with adjuvant MAPKi or ICI therapy. These encouraging results will likely change the treatment recommendations, but also pose new challenges: Which patients should receive which drug to what end? The goal of adjuvant therapy is to improve overall survival by preventing widespread metastatic disease.4 First attempts using interferon-based adjuvant therapies led to only a small impact on overall survival, limiting acceptance and usage.5 More recently, adjuvant therapy with ipilimumab improved overall survival, but severe toxicity prevented submission to the European Medicines Agency.6 The recently published trials1-3 with adjuvant MAPKi and ICI therapies show more promising results, but the efficacy data are currently based on recurrence-free survival and mature overall survival data is not yet available. However, statistical analyses indicate that recurrence-free survival and overall survival are highly correlated.7 Thus, although sufficient follow-up is lacking, a positive impact of adjuvant therapy on overall survival can now be assumed. When interpreting overall survival data from adjuvant clinical trials, post-recurrence therapies have to be taken into account, as they may influence and confound the end point. The more mature data for adjuvant ipilimumab therapy sheds some light on this bias: post-recurrence survival was not different between patients in the placebo and the ipilimumab arm,6 indicating that overall survival benefit is due to adjuvant and not post-trial therapy. The protocol of KEYNOTE-054 also addressed another essential question: Does it make a survival difference to use the ICI pembrolizumab in adjuvant therapeutic settings or at the time of nonresectable recurrence? Data to answer this question have not yet been presented but are needed to better understand the impact of adjuvant therapy on patient outcomes. Overall survival data are also essential to fully evaluate the risk–benefit ratio of adjuvant therapies. Patients might experience adverse events impairing quality of life. In the case of ICI, permanent loss of hormone production is possible, requiring life-long substitution (e.g. insulin, hydrocortisone).8 In addition, no safety data on post-treatment fertility are available for either ICI or MAPKi. Besides these individual medical risks, the economic burden of broad application of adjuvant, high-priced therapeutics is a challenge to the healthcare system. Proper patient selection will be the key to facing these difficulties. It will be crucial to identify patients with a high risk for recurrence of metastatic disease and those with characteristics associated with even greater benefit than the overall study population. The current American Joint Committee on Cancer (AJCC) classification provides an evidence-based recommendation for melanoma staging.9 The recent adjuvant trials were recruited according to AJCC 2009; in contrast, the 2017 AJCC classification is now the norm. Essential features still include tumour thickness, ulceration and nodal status. In addition, mitotic rate and sentinel lymph node tumour burden might identify patients with higher risk of death. Unfortunately, patients with stage IIC disease were not included in any of the three adjuvant trials. However, mortality in patients at stage IIC is higher than at stage IIIA and similar to patients with stage IIIB melanoma,9 indicating the need for adjuvant clinical trials in this patient subpopulation. Recommendations for adjuvant therapy will be more challenging in patients with BRAFV600E/K-mutant melanoma, where clinicians have the choice between MAPKi and ICI, than in the nonmutant, BRAFwt melanoma population, in which adjuvant therapy with ICI is the only therapeutic option. Looking at recurrence-free survival, targeted therapy with MAPKi seems to be superior (free of recurrence and alive at 12 months: 88% for MAPKi vs. 75% for pembrolizumab vs. 71% for nivolumab). However, it remains unclear if this early advantage will last and translate into superior overall survival. In metastatic settings, the indirect comparison of overall survival in patients receiving MAPKi or ICI points to a crossing of survival estimates, favouring ICI.10 Although there are no prospective head-to-head overall survival data, available studies indicate that ICI might out-run MAPKi in metastatic melanoma. Despite these considerations, currently clinicians will not be able to clearly identify patients with BRAFV600E/K-mutated melanoma having greater benefit from either adjuvant ICI or MAPKi. Obvious contraindications like active pre-existing autoimmunity for either measure exist in only a minor fraction of patients with BRAFV600E/K-mutated melanoma. Counselling patients is challenging, especially when solid evidence is lacking, and must currently still be made on a patient-to-patient basis. Comparable with the dramatic improvement often seen for ICI and MAPKi in the treatment of metastatic melanoma, adjuvant therapy is now a reality heralding a new era of melanoma therapy. While promising and likely beneficial for numerous patients, individual counselling will become more complicated in the near future. These challenges should be considered as opportunities. Supported by Vienna Science and Technology Fund (LS16- 063). B.S. is on the advisory board or has received honoraria from Bristol-Myers Squibb, Incyte, MSD Sharp & Dohme, Novartis and Roche; research funding from Bristol-Myers Squibb and MSD Sharp & Dohme and travel support from Amgen, Bristol-Myers Squibb, Novartis, Pierre Fabre Pharmaceuticals and Roche. T.W. declares no conflicts of interests.