Treatment of Metastatic Melanoma at First Diagnosis: Comparison
Please note this is a comparison between versions V2 by Catherine Yang and V1 by Miguel-Angel Berciano-Guerrero.

Metastatic melanoma (MM) is a pathological entity with a very poor prognosis that had a low response rate to systemic treatments. In fact, the aggressiveness of melanoma is different depending on whether it debuts directly as metastatic disease or if what occurs is a relapse after a first diagnosis at an early stage, although the biological determinants are largely unknown. Another key aspect in the clinical management of metastatic melanoma at first diagnosis strives in the different prognosis of melanoma of unknown primary (MUP) compared to melanoma of known primary (MPK).

  • metastatic melanoma
  • first diagnosis
  • MUP

1. Introduction

Previously, many efforts have been made to understand patterns of disease progression, providing information on risks that have helped improve monitoring and the efficacy of new adjuvant treatments [4,5,6,7,8][1][2][3][4][5]. More recently, additional studies are aiming to improve not only survival in the initial stages, with better diagnosis and adjuvant therapies that are more effective, but also the treatment of unresectable or metastatic disease, regardless of the initial stage at diagnosis. The arrival of immune checkpoint inhibitors (ICI) and targeted therapy (TT) with BRAF inhibitors/MEK inhibitors (BRAFi/MEKi) has triggered a paradigm shift, facilitating a better understanding of the molecular biology of these tumors. Melanoma is, to date, the most immunogenic tumor [9][6]. The high rate of neoantigens allows the tumor cells to respond better to therapies that act on the immune system and the tumor microenvironment (TME). Moreover, the immunological perturbation induced by ICI could influence the response to other subsequent therapies, suggested by better outcomes of TT after ICI [10][7]. However, more studies are needed to confirm this strategy.

2. Epidemiology of MM at First Diagnosis

Melanoma is a tumor with a low incidence rate, but high mortality. For 2022, the estimated number of new cases of melanoma in situ or invasive in the United States is 97,920 and 99,780, respectively, with an estimated number of deaths of 7650 patients. This indicates an annual decrease of 4%, due to recent improvements in treatments in both adjuvant and advanced disease treatments [11][8]. This trend can be observed in other countries in the world. Survival rates according to initial disease stage have been extensively described in large cohorts of patients [12[9][10][11][12],13,14,15], and the loss of efficacy towards advanced stages is a consolidated event (Table 1).
Table 1.
 Studies reporting data on metastatic melanoma at initial diagnosis.
36][26]. Therefore, initial molecular characterization may also contribute to predict such behavior and how targeted therapy efficacy is affected by that. Importantly, this information is so far lacking in the pivotal studies of this therapeutic approach. Furthermore, new strategies with targeted therapy, such as triplet treatments that include targeted therapy and immunotherapy, may provide data on the clinical evolution and response to treatment in these MM patients. However, data on this subpopulation are thus far not available in these combination strategies trials such as the COMBI-i study, which combines spartalizumab with dabrafenib and trametinib, or the IMspire150 study that combines atezolizumab with vemurafenib and cobimetinib [37,38][27][28]. Similarly, MUP patients were included in the targeted therapy pivotal studies, although their outcomes were not reported. Therefore, the efficacy of these treatments in this subgroup of patients remains to be specified.

4.2. Immunotherapy

The data from the pivotal studies with approved immunotherapeutic drugs that constitute the first line of treatment for metastatic melanoma are presented in Table 32.
Table 32. Main pivotal studies of currently approved immunotherapy for metastatic melanoma.
Main pivotal studies of currently approved immunotherapy for metastatic melanoma.


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