Neoadjuvant Immune Checkpoint Inhibitor Therapy in Melanoma: Efficacy, Safety and Timing

Abstract

The introduction of effective systemic therapies has significantly changed the treatment of stage III and IV melanoma. Both immune checkpoint inhibitors and targeted therapies have improved recurrence-free survival in the adjuvant setting. Recent interest has sparked for neoadjuvant systemic therapy with immune checkpoint inhibitors. The intended benefit of pre-operative treatment with immunotherapy is amongst others to enable tailoring of the surgery and adjuvant systemic therapy according to the treatment response. Most importantly, recurrence-free survival might be improved by neoadjuvant systemic therapy over the current standard of care of surgery followed by adjuvant systemic therapy. The first phase I and II trials investigating anti-PD1 inhibitors, both as a single agent and in combination with anti-CTLA-4 inhibitors or other therapeutic agents, have shown promising results. Pathological complete response on neoadjuvant systemic therapy seems a valid surrogate endpoint for relapse-free and overall survival. Pathological complete response rates in these trials vary between 30 and 70%. The optimal dose with respect to efficacy and toxicity and the interval between systemic and surgical treatment remain important issues to address. Accumulating follow-up data and ongoing phase III studies must prove if neoadjuvant systemic therapy is superior to surgery followed by standard-of-care adjuvant therapy.