Does systemic drug therapy improve progression-free, overall survival in unresectable stage III and stage IV melanoma?

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The management of unresectable stage III and stage IV melanoma (metastatic or advanced melanoma) has been revolutionised with effective drug therapies that target either i) checkpoints on T-cells to induce T-cell mediated cancer-cell death or ii) the mitogen activated protein kinase (MAPK) pathway in melanoma cancer cells, particularly patients with V600 BRAF mutant melanoma. The former is referred to as immunotherapy and the latter as targeted therapy, these are discussed in more detail in their own sections (see bottom of this page). Whereas the 1-year overall survival (OS) was 25–35% for decades,[1] rapidly decreasing to <5% at 5 years, the 1-year OS is now 70–75% for both classes of systemic drug therapies. However, it is the longer-term control of advanced melanoma that is noteworthy, with landmark 3-year OS >60% for combination checkpoint inhibitor immunotherapy,[2] with maintenance of quality of life.[3]

Figure 1. Systemic drug therapy flowchart (click to enlarge)

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Note: the options in the flowchart are not listed in order of preference.


This section summarises the current highest level of evidence for the efficacy of these drug therapies in patients with advanced melanoma, as well as provide recommendations and practice points for clinicians treating these patients. With the variety of therapies available, as well as the available local therapies (surgery, radiotherapy, intralesional therapy [injection of a drug therapy directly into a melanoma metastasis] and experimental topical therapies), treatment algorithms must be considered carefully for each individual patient, including the choice of first-line drug therapy, the sequencing of therapies and the patient’s eligibility for clinical trials. Due to the high incidence of brain metastases in patients with advanced melanoma, and the activity of systemic drug therapies in this patient population based on phase II trials, a separate section has been developed for these guidelines providing guidance and a summary of brain metastases evidence (see bottom of page). Given the increasing number of options and the complexity of the management of patients with advanced melanoma, it is strongly recommended that all patients be managed in the context of a multidisciplinary team of clinicians with experience in the management of melanoma. Specifically, patients requiring drug therapy should be managed by medical oncologists with expertise in managing associated toxicities

This section of the guideline does not provide evidence for drug therapy in metastatic uveal melanoma, and these patients should be considered for clinical trials given the lack of active drug therapies.

This section of the guideline is supported by evidence from a systematic review undertaken in March 2017. The systematic review addressed the research question: Does systemic drug therapy improve progression free and/or OS in unresectable stage III and stage IV melanoma? The systematic review included evidence published since 2010 and was limited to the inclusion of meta-analyses (of phase III randomised controlled trials [RCT]), systematic reviews (of phase III RCTs), and individual phase III RCTs. The scope of the systematic review was limited to the mentioned criteria due to the large number of trials in this field. Additional evidence that was outside the scope the systematic review but considered important has been incorporated in the narrative section. Evidence included from outside the systematic review is identified with an asterisk (*) following the reference.

Drug therapies in patients with advanced melanoma

See the following sections:

Systemic drug therapy in melanoma brain metastases

Systemic drug therapies are active in melanoma brain metastases. Management of melanoma brain metastases requires a multidisciplinary approach. Evidence for local therapies and systemic drug therapy in the management of brain metastases is covered separately, see the Brain metastases section.


  1. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009 Dec 20;27(36):6199-206 Available from:
  2. Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med 2017 Sep 11 Available from:
  3. Schadendorf D, Larkin J, Wolchok J, Hodi FS, Chiarion-Sileni V, Gonzalez R, et al. Health-related quality of life results from the phase III CheckMate 067 study. Eur J Cancer 2017 Sep;82:80-91 Available from: