Adjuvant Therapy for High-Risk Melanoma: An In-Depth Examination of the State of the Field

SIMPLE SUMMARY: Patients with stage IIB-IV melanoma who have had surgery are recommended to receive systemic adjuvant therapy, intended to target the residual micro-metastatic disease and reduce the risk of melanoma relapse and death from melanoma. Multiple adjuvant therapy regimens have been tested over the past three decades leading to regulatory approvals. Due to significant improvements in relapse-free survival, programmed cell death protein 1 (PD-1) blockades and BRAF-MEK inhibitors (for BRAF mutant melanoma) are currently used as the standard-of-care adjuvant treatments for surgically resected stage III-IV melanoma. In the US, pembrolizumab has achieved regulatory approval as an adjuvant therapy for resected stage IIB-IIC melanoma, while nivolumab is currently under FDA review for this indication. This review examines melanoma’s phase III adjuvant treatment trials, focusing on the latest updates. It also reviews the role of biomarkers in potentially individualizing adjuvant therapy and summarizes the main limitations and future directions of adjuvant therapy options for high-risk melanoma. ABSTRACT: The consideration of systemic adjuvant therapy is recommended for patients with stage IIB-IV melanoma who have undergone surgical resection due to a heightened risk of experiencing melanoma relapse and mortality from melanoma. Adjuvant therapy options tested over the past three decades include high-dose interferon-α, immune checkpoint inhibitors (pembrolizumab, nivolumab), targeted therapy (dabrafenib-trametinib for BRAF mutant melanoma), radiotherapy and chemotherapy. Most of these therapies have been demonstrated to enhance relapse-free survival (RFS) but with limited to no impact on overall survival (OS), as reported in randomized trials. In contemporary clinical practice, the adjuvant treatment approach for surgically resected stage III-IV melanoma has undergone a notable shift towards the utilization of nivolumab, pembrolizumab, and BRAF-MEK inhibitors, such as dabrafenib plus trametinib (specifically for BRAF mutant melanoma) due to the significant enhancements in RFS observed with these treatments. Pembrolizumab has obtained regulatory approval in the United States to treat resected stage IIB-IIC melanoma, while nivolumab is currently under review for the same indication. This review comprehensively analyzes completed phase III adjuvant therapy trials in adjuvant therapy. Additionally, it provides a summary of ongoing trials and an overview of the main challenges and future directions with adjuvant therapy.