We are doing this study to compare the safety and effects of stopping the standard melanoma treatments of nivolumab + pembrolizumab or nivolumab + relatlimab at different times. We hope this study will help us discover certain markers from imaging and biopsies that can signal when it is the appropriate time to stop therapy.

Advanced Melanoma

Adults ages 18+ who:

• Are diagnosed with advanced melanoma that is unresectable stage IIIB-IV; OR are diagnosed with mucosal melanoma that is unresectable stage III or regional/distant metastatic disease
• Have been receiving standard anti-PD-1 therapy for at least 1 year
• Do not have any known inability to take any of the study drugs (nivolumab + pembrolizumab or nivolumab + relatlimab)

For more information about who can join this study, please contact the study team at nick.jeffries@duke.edu.

If you choose to join this study, you will have certain procedures done to determine when you should stop using your current therapy. The steps that will be taken are as follows:

• After you hit the 1-year mark of taking your standard therapy, we will schedule you to have a PET/CT scan. If there is no evidence of disease on this scan, you will stop the therapy. If there is evidence that disease might still be present, we will schedule you for a biopsy.
• If you have the biopsy done, the results will guide what happens next. If there are no active cancer cells detected in the biopsy, you will discontinue your therapy. If the biopsy is positive for cancer cells, you will continue your current therapy for at least 1 more year.

Currently, the standard therapy is to continue taking anti-PD-1 therapy for about 2 years after a PET/CT scan is negative for evidence of disease. We hope this study will let us know if it is not necessary to continue on this regimen for that long.