Background: Neoadjuvant therapy (NAT) has emerged as a promising strategy to treat resectable melanoma patients by generating a robust immune response and longer immunologic memory. We performed a systematic review and meta-analysis evaluating the survival benefit of NAT compared to standard adjuvant therapy (AT) for melanoma patients. Methods: We searched for randomized clinical trials (RCT) comparing NAT versus AT in resectable stages IIIB/C or IV melanoma patients on PubMed, Scopus, and Cochrane Library databases. We assessed event-free survival (EFS), distant metastasis-free survival (DMFS), overall survival (OS), and safety. Studies included were limited to RCTs with an adjuvant control arm and reporting at least one of the outcomes of interest. Heterogeneity was examined with the I² statistics, and the random effects model was fitted. Results: Four RCTs met inclusion criteria for a total of 504 patients. Most patients had stage IIIB/C (79.1%), and received NAT with immunotherapy (66%), target therapy (4.2%) and talimogene laherparepvec (TVEC) (29.8%). In the pooled analysis of 2-year follow-up: 71.3% of patients in the NAT arm and 53.2% in AT arm were event-free [Risk Ratio (RR): 0.57 95%Cl 0.39-0.83 p=0.003]. Albeit the difference in therapies, NAT decreased by 44% the risk of death compared to AT, with 89.4% and 81.2% of patients alive at two years, respectively (RR 0.56 95%Cl 0.36-0.87 p=0.01). DMFS was reported in three studies (n=191). Patients on NAT had numerically higher DMFS rate (44%) compared to AT (28.6%) (p=0.23). Two studies (n=170) have published 5-year follow-up results: OS rate has remained statistically significant, favoring NAT (RR 0.58 95%Cl 0.34-0.97 p=0.04). Significant differences were not observed in EFS (p=0.06) and DMFS (p=0.08). Adverse events were similar in both groups, and there were no treatment-related deaths. In these studies, there were no significant delays in surgery due to toxicity or unexpected perioperative complications. Combined immunotherapy caused the highest incidence of grade 3/4 toxicity (90%) among the therapies. Conclusions: This systematic review and meta-analysis indicate a significant survival benefit from NAT for stages IIIB/C and resectable stage IV melanoma. NAT induces better anti-tumor activity, leading to improved EFS and OS compared to AT, with similar safety profile. Phase 3 clinical trials with longer follow-up are warranted.

^†Mean or median. N: number; y: year; Ph: phase; D/T: Dabrafenib and Trametinib; Ipi/Nivo: Ipilimumab and Nivolumab; Pem: Pembrolizumab.