Table 8. Standard Treatment Options for Melanoma continued...
Therapies that have improved OS in patients with recurrent or metastatic disease are now being tested as adjuvant therapy in clinical trials, including NCT01274338, NCT01667419, and NCT01682083.
A completed, multicenter, phase III randomized trial (SWOG-8593) of patients with high-risk primary stage I limb melanoma did not show a disease-free survival or OS benefit from isolated limb perfusion with melphalan, when compared with surgery alone.
Systematic Treatment for Unresectable Stage III, Stage IV, and Recurrent disease
Although melanoma that has spread to distant sites is rarely curable, treatment options are rapidly expanding. Two approaches-checkpoint inhibition and targeting the mitogen-activated protein kinase pathway-have demonstrated improvement in OS in randomized trials in comparison to dacarbazine (DTIC). Although none appear to be curative when used as single agents, early data of combinations are promising. Given the rapid development of new agents and combinations, patients and their physicians are encouraged to consider treatment in a clinical trial for initial treatment and at the time of progression.
Checkpoint inhibitors: Ipilimumab has demonstrated an improvement in progression-free survival (PFS) and OS in international, multicenter, randomized trials in patients with unresectable or advanced disease, resulting in FDA approval in 2011. In an international, multicenter, randomized trial, pembrolizumab received accelerated approval in 2014 for demonstrating durable responses in patients whose disease had progressed after they received ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Multiple phase III trials of PD-1 (programmed cell death-1) and PD-L1 (programmed death-ligand 1) checkpoint inhibitors alone and in combination (e.g., with ipilimumab) are in progress to assess their ability to improve PFS and OS.
Interleukin-2 (IL-2): IL-2 was approved by the FDA in 1998 on the basis of durable complete response (CR) rates in a minority of patients (6%-7%) with previously treated metastatic melanoma in eight phase I and II studies. Phase III trials comparing high-dose IL-2 with other treatments and providing an assessment of relative impact on OS have not been conducted.
Signal transduction inhibitors
Studies to date indicate that both BRAF and MEK inhibitors can significantly impact the natural history of melanoma, although they do not appear to be curative as single agents.