Neoadjuvant immune checkpoint inhibition (ICI) has officially arrived as the standard of care for resectable stage III melanoma, displacing the older adjuvant-only approach. Two pivotal trials drove this shift: SWOG S1801, which showed a 72% vs. 49% two-year event-free survival (EFS) favoring neoadjuvant pembrolizumab, and NADINA, which demonstrated a 77.3% vs. 55.7% 24-month EFS with neoadjuvant ipilimumab plus nivolumab. NADINA's response-adapted design was a standout—patients achieving a major pathologic response (MPR) went straight to surveillance, sparing nearly two-thirds of patients from a full year of adjuvant therapy.

Pathologic response is proving to be a powerful prognostic tool. Patients achieving a complete pathologic response had an 18-month recurrence-free survival of 94.9%, while non-responders faced a much grimmer 55.1%—highlighting an urgent need for better salvage strategies. Newer combinations like relatlimab plus nivolumab are showing comparable efficacy with fewer toxic side effects, and surgical de-escalation trials are testing whether full lymph node dissection can be safely skipped in strong responders.

Key Takeaways:

• Neoadjuvant ICI is now preferred over adjuvant-only therapy for resectable stage III melanoma
• Pathologic response guides post-op treatment decisions and predicts long-term outcomes
• Relatlimab + nivolumab may offer similar efficacy with a better safety profile than ipilimumab + nivolumab
• Non-responders remain a high-risk group with no clearly effective salvage strategy yet

Why it matters: This shift toward neoadjuvant immunotherapy isn't just about better survival numbers—it's about treating smarter. By reading the tumor's response before surgery, clinicians can personalize follow-up care, reduce unnecessary treatment, and minimize surgical morbidity, moving melanoma management into a more precise, patient-centered era.