Background
Phase II/III RCT (SWOG S1801), N=313 resectable stage IIIB-IV or unresectable stage IIIC-IV (made resectable) melanoma (AJCC 8th ed). Any BRAF status, no prior systemic treatment. Stratified by disease stage, BRAF status, region. Enrolled 2019-2021 across US SWOG cooperative group centers.
Interventions and follow up
Arm A: Neoadjuvant pembrolizumab 200 mg q3wk × 3 doses → surgery → adjuvant pembrolizumab 200 mg q3wk × 15 doses (~18 months total)
Arm B: Surgery → adjuvant pembrolizumab 200 mg q3wk × 18 doses (~18 months, adjuvant-only)
Primary endpoint: Event-free survival (EFS)
mFollow up: 14.7 months
Arm B: Surgery → adjuvant pembrolizumab 200 mg q3wk × 18 doses (~18 months, adjuvant-only)
Primary endpoint: Event-free survival (EFS)
mFollow up: 14.7 months
Results
2-yr EFS: 72% vs 49%, HR 0.58, 95% CI 0.39-0.87, P=.004
Major pathological response (Arm A, ≥90% regression): 35%
OS: not mature at primary analysis
Major pathological response (Arm A, ≥90% regression): 35%
OS: not mature at primary analysis
Adverse events
Grade ≥3 immune-related AEs: 14% (Arm A) vs 10% (Arm B)
Surgical delay due to AE: 7% in neoadjuvant arm
Surgical resection rate: 84% vs 93%
Cumulative toxicity: comparable; neoadjuvant addition did not substantially increase it
Surgical delay due to AE: 7% in neoadjuvant arm
Surgical resection rate: 84% vs 93%
Cumulative toxicity: comparable; neoadjuvant addition did not substantially increase it
Conclusions
Neoadjuvant pembrolizumab followed by surgery and adjuvant pembrolizumab significantly improved 2-year EFS vs adjuvant pembrolizumab alone (72% vs 49%, HR 0.58, P=.004) in resectable melanoma, the first randomized evidence for neoadjuvant IO superiority over adjuvant-only IO.
Key Limitations
Short median follow-up (14.7 months); OS immature. Phase II portion may not be powered for all subgroup analyses. Lower resection rate in neoadjuvant arm (84% vs 93%) suggests some patients progressed before surgery; these worse-prognosis patients are included in EFS analysis. Major pathological response of 35% lower than ~57% pCR with neoadjuvant ipi+nivo (OpACIN-neo, NADINA), supporting potential superiority of dual checkpoint blockade. No standard-of-care arm without systemic therapy.
Clinical Context
SWOG S1801 provided the first phase III-level randomized evidence supporting neoadjuvant IO over adjuvant-only IO for resectable melanoma, accelerating the shift toward neoadjuvant approaches. Concurrent NADINA (NEJM 2024) showed even greater EFS benefit with neoadjuvant ipi+nivo over adjuvant nivo (HR 0.32) using a response-adapted approach. Together, S1801 and NADINA have shifted ESMO guidelines toward preferring neoadjuvant IO for resectable stage III melanoma. S1801 used pembrolizumab monotherapy; NADINA used ipi+nivo (not directly compared neoadjuvantly), and practice is increasingly moving toward neoadjuvant ipi+nivo given more robust pCR and EFS data.