New paradigms in the management of melanoma throughout various stage of the disease

New paradigms in the surgical management of primary melanoma are currently focused on reducing the margins of excision of the primary and reducing the use of sentinel lymph node biopsy procedures (SLNB) because of the excessive use of the procedure in stage I-IIA melanoma. Gene expression profiles (GEPs), particularly the ClinicoPathologic (CP)-GEPs algorithm, are highly successful at identifying stage I/II patients who will relapse in spite of a negative SLNB. Regarding systemic adjuvant therapies, the new paradigm for stage III melanomas is focused on neoadjuvant anti-PD1-based therapies because of their superior results compared to adjuvant treatments. Moreover, patients with a major pathologic response (MPR) in the lymph nodes do not need adjuvant anti-PD1 for 9 months postoperatively. The PRADO trial piloted surgical de-escalation for MPR patients with an Index Lymph Node (ILN) resection only. MSLT-3 randomizes patients between TLND and ILN to definitively establish this. In cases of advanced disease, the Dreamseq trial has formally demonstrated that in BRAF mutant patients, by far the best results are obtained by starting with anti-CTLA4 + anti-PD1 first as opposed to starting with BRAF/MEK inhibitor combinations. The combination with anti-LAG3 may provide additional benefit, as it prolongs T-effector cell life span. Regarding the anti-PD1 refractory problem, relatively modest progress has been made over the last decade with the combination of anti-CTLA4+anti-PD1, which is mostly used with a 25–30% overall response rate (ORR). Adoptive Cellular Therapy with Tumour-Infiltrating Lymphocytes (TILs) may provide better results in selective patient populations.