Neoadjuvant immune checkpoint inhibitors for patients with resectable stage III/IV melanoma: a nationwide real-life study in France (NEOMEL).

Abstract

Despite the clear therapeutic benefits of neoadjuvant treatment (NT) with immune checkpoint inhibitors (ICIs) in clinical trials, the efficacy of NT with ICIs (NT-ICI) and the optimal regimen for patients with resectable metastatic melanoma (RMM) remain to be confirmed in real life. To assess the efficacy and safety of NT-ICI among patients with RMM in real life. NEOMEL is a French retrospective multicentric cohort study. Dermato-oncologists from the French Groupe de Cancérologie Cutanée (Cutaneous Cancer Group) included patients treated with NT-ICI for RMM (stage III or IV, American Joint Committee on Cancer 8th edn) between July 2016 and April 2024. Patients were treated either with NT anti-programmed cell death protein-1 (anti-PD-1) monotherapy or with the combination of anticytotoxic T-lymphocyte-associated protein-4 (anti-CTLA-4) plus anti-PD-1 [1 mg kg-1 ipilimumab (IPI) and 3 mg kg-1 nivolumab (NIVO) or 3 mg kg-1 IPI and 1 mg kg-1 NIVO]. The primary endpoint was the pathological complete response (pCR) rate. The secondary endpoints were pathological response according to the International Neoadjuvant Melanoma Consortium criteria, radiological response, the occurrence of immune-related adverse events (irAEs) including those of ≥ grade 3 and outcomes with recurrence-free survival (RFS) and event-free survival (EFS). Among the 174 included patients, 149 (86%) underwent surgery. NT-ICI achieved a high pCR rate of 43% [95% confidence interval (CI) 34.9-51.3], including 44.7% (95% CI 35.4-54.3) with NT-anti-PD-1 and 37.1% (95% CI 21.5-55.1) with NT-IPI-NIVO (P = 0.427). The major (complete + near complete) pathological response rate was 53.2%. Radiological responses were observed in 50% of patients, including 12 radiological complete responses, of whom 11 were also pCRs. Severe irAEs occurred more frequently with NT-IPI-NIVO (24.4%) compared with NT-anti-PD-1 (3.1%) (P < 0.001). The median RFS was 29.61 months [95% CI 27.70-not reached (NR)] with significantly higher RFS in patients with pCR than no pCR [hazard ratio 0.218 (95% CI 0.082-0.583); P = 0.0009]. The median EFS was 35.8 months (95% CI 29-NR). In this retrospective real-life study, the efficacy of NT-ICI is confirmed in patients with RMM, achieving high pathological response rates. However, dual checkpoint inhibition with IPI-NIVO was associated with a higher risk of severe irAEs. These findings underscore the relevance of NT-ICI for RMM in clinical practice and require further confirmation.