Abstract
Survival of macroscopic stage III melanoma is poor. Five-year overall survival and relapse-free survival rates for surgery alone range from 40 to 59% and 30 to-39%, respectively. The current standard of care is therapeutic lymph node dissection (TLND) followed by a year of adjuvant systemic therapy. Multiple phase 2 trials have shown that neo-adjuvant immunotherapy induces major pathologic response (MPR) rates (pathologic complete response (pCR): pCR, 0% viable tumour cells; near-pCR, <10% viable tumour cells), which translate into durable relapse free survival rates. Single agent anti-PD-1 achieves 20-30% MPR, the combination of ipilimumab and nivolumab doubles the MPR rates to 50-60%. The OpACIN trial demonstrated that neoadjuvant immunotherapy induced both higher numbers and a broader repertoire of tumour-resident T-cells in peripheral blood compared with adjuvant immunotherapy. Very recently, the randomised phase 2 trial S1801 reported its first interim results. S1801 compared TLND, followed by 18 courses of adjuvant pembrolizumab, to three courses of neoadjuvant pembrolizumab, followed by surgery and 15 adjuvant doses. With a median follow-up of 14 months, a 23% EFS rate benefit was observed. The ongoing phase 3 NADINA trial randomises patients between TLND + one year of adjuvant nivolumab (control arm) or 2 courses of neoadjuvant therapy with ipilimumab + nivolumab, followed by adjuvant therapy only for non-MPR patients. There is rapid, consistent, and accumulating evidence generated from all phase 1 and phase 2 trials, indicating clinical superiority of neoadjuvant immunotherapy over adjuvant systemic therapy for macroscopic stage III melanoma. Therefore, payers should consider neoadjuvant immunotherapy for reimbursement as this approach is the best option for our patients, and classify it as the best medical practice.