Neoadjuvant Pembrolizumab Improves Event‑Free Survival in Resectable Melanoma

Trial Evidence

• In the SWOG S1801 phase 2 trial, patients receiving three neoadjuvant doses of pembrolizumab followed by surgery and 15 adjuvant doses achieved a 2‑year event‑free survival (EFS) of 72% (95 % CI 64‑80 %) versus 49% (95 % CI 41‑59 %) with adjuvant‑only therapy, an absolute improvement of 23 % (95 % CI 11‑35 %)【1】【2】【3】.
• Median follow‑up was 14.7 months【1】【2】【3】.

Patient Eligibility

• Eligible participants had clinically detectable, measurable, resectable stage IIIB‑IVC cutaneous, acral, or mucosal melanoma【2】【1】.
• Disease had to be resectable with either clinically positive lymph nodes or oligometastatic stage IV involvement【1】【3】.
• Only 23 patients (≈ 5 % of the cohort) had stage IV disease, representing a small subset of the trial population【1】【4】.

Treatment Regimen

• Neoadjuvant phase: Pembrolizumab 200 mg IV every 3 weeks for up to 3 doses (≈ 9 weeks)【1】【2】【3】.
• Adjuvant phase: Pembrolizumab 200 mg IV every 3 weeks for 15 additional doses, for a total of 18 doses over roughly 1 year【1】【2】【3】【5】.
• The control arm received surgery followed by the same 18‑dose adjuvant schedule, ensuring identical total pembrolizumab exposure【1】【2】.

Clinical Outcomes

Event‑Free Survival

• The neoadjuvant‑adjuvant approach yielded a 23 % absolute increase in 2‑year EFS compared with adjuvant‑only therapy【1】【2】.

Safety

• Grade ≥ 3 treatment‑related adverse events occurred in 12 % of patients receiving neoadjuvant‑adjuvant therapy versus 14 % in the adjuvant‑only group【1】【3】.

Guideline Recommendations

ASCO (2023)

• The American Society of Clinical Oncology strongly recommends up to three neoadjuvant pembrolizumab courses (200 mg q3 weeks) followed by surgical resection and up to fifteen adjuvant courses for clinical stage IIIB‑IV resectable melanoma【1】【4】.
• The Expert Panel notes minimal additional harm because total pembrolizumab cycles are identical to the standard adjuvant regimen【1】【4】.

NCCN (2024)

• The National Comprehensive Cancer Network designates pembrolizumab as a Category 2A preferred neoadjuvant regimen for:
• NCCN now generally prefers neoadjuvant therapy over therapeutic lymph‑node dissection followed by adjuvant systemic treatment【5】【3】.

Evidence Gaps & Limitations

• Overall survival data have not yet been reported for the trial cohort【1】【2】.
• Hazard ratios for EFS were not provided; only absolute 2‑year differences are available【1】【2】.
• The small number of stage IV participants (23 patients) limits the robustness of conclusions for this subgroup, although the ASCO panel believes they would benefit【1】【4】.

Neoadjuvant Immunotherapy for Stage 3 Melanoma

Introduction to Neoadjuvant Immunotherapy

• The National Comprehensive Cancer Network recommends neoadjuvant immunotherapy followed by surgery and adjuvant therapy for resectable stage III melanoma with clinically positive lymph nodes, as it has shown to improve event-free survival compared to upfront surgery plus adjuvant therapy alone 6, 7, 8.

Recommended Neoadjuvant Regimens

• The American Society of Clinical Oncology suggests pembrolizumab 200 mg IV every 3 weeks for 3 doses before surgery, followed by surgical resection and adjuvant pembrolizumab 200 mg IV every 3 weeks for 15 additional doses, with a 2-year event-free survival of 72% and grade 3+ adverse events in 12% of patients 6, 9, 8.
• The National Comprehensive Cancer Network recommends "flip-dose" nivolumab/ipilimumab as a preferred option, with nivolumab 3 mg/kg + ipilimumab 1 mg/kg IV every 3 weeks for 2 doses before surgery, followed by surgical resection and adjuvant therapy based on pathologic response, with a pathologic response rate of 77% and 3-year relapse-free survival of 82% 6, 9, 10.

Surgical Management and Adjuvant Therapy

• The American Society for Radiation Oncology recommends complete therapeutic lymph node dissection of the submandibular/cervical basin 3-6 weeks after completing neoadjuvant therapy, and adjuvant radiation therapy to the cervical/submandibular nodal basin for high-risk features 11, 6, 7.
• The National Comprehensive Cancer Network suggests that the pathologic response to neoadjuvant therapy should guide subsequent adjuvant treatment decisions, with major pathologic response (≥90% tumor necrosis) considering observation or anti-PD-1 monotherapy, and partial or no pathologic response considering complete therapeutic lymph node dissection plus adjuvant anti-PD-1 therapy 7, 8, 12.

Critical Baseline Workup and Common Pitfalls

• The National Comprehensive Cancer Network recommends complete staging before initiating neoadjuvant therapy, including high-resolution MRI of the neck with contrast, CT chest/abdomen/pelvis with contrast, brain MRI with contrast, and consideration of PET scan for distant metastases, as well as serum LDH and BRAF mutation testing 11, 13, 14.
• The American Society of Clinical Oncology advises against delaying surgery beyond 12 weeks from neoadjuvant therapy initiation, using ipilimumab monotherapy or high-dose interferon, and proceeding with neoadjuvant therapy without confirming resectability 6, 7, 8, 15.

Adjuvant and Neoadjuvant Anti‑PD‑1 Therapy for Resected Stage IIIB Melanoma

1. Guideline‑endorsed anti‑PD‑1 agents (Category 1)

• Pembrolizumab 200 mg IV every 3 weeks for up to 12 months (18 doses) is the standard adjuvant regimen recommended by the NCCN and ASCO. 16
• Nivolumab 240 mg IV every 2 weeks or 480 mg IV every 4 weeks for up to 12 months is an equally endorsed standard adjuvant regimen. [16][17]

2. Efficacy of adjuvant pembrolizumab

• In the KEYNOTE‑054 trial, pembrolizumab improved recurrence‑free survival (RFS) versus placebo with a hazard ratio (HR) = 0.57 (95 % CI 0.46‑0.70; p < 0.001) in patients with resected stage III melanoma. Level of evidence: Category 1. [16][17]
• One‑year RFS was 75.4 % with pembrolizumab compared with 61.0 % with placebo. Level of evidence: Category 1. 17
• Grade 3‑4 treatment‑related adverse events occurred in 14.4 % of pembrolizumab‑treated patients. Level of evidence: Category 1. 17

3. Efficacy of adjuvant nivolumab

• In the CheckMate 238 trial, nivolumab demonstrated superior RFS to high‑dose ipilimumab in stage IIIB/C disease (HR = 0.66; 95 % CI 0.53‑0.81). Level of evidence: Category 1. 17
• Grade 3‑4 adverse events were observed in 14.4 % of patients receiving nivolumab, markedly lower than the 45.9 % rate with ipilimumab. Level of evidence: Category 1. 17

4. Comparative safety of anti‑PD‑1 agents vs ipilimumab

• The NCCN panel no longer recommends ipilimumab as first‑line adjuvant therapy for stage III melanoma because of its substantially higher toxicity (grade 3‑4 AEs = 45.9 % vs 14.4 % with nivolumab). Level of evidence: Category 1. [16][17]18
• Anti‑PD‑1 agents (pembrolizumab or nivolumab) provide better RFS than ipilimumab while maintaining a more favorable safety profile. Level of evidence: Category 1. [16][17]

5. Preference for anti‑PD‑1 over BRAF/MEK targeted therapy

• In the COMBI‑AD trial, dabrafenib + trametinib yielded an RFS HR = 0.47 (95 % CI 0.39‑0.58) versus placebo in BRAF‑mutant patients, but anti‑PD‑1 therapy is generally preferred because it offers comparable efficacy with a superior toxicity profile and does not require mandatory BRAF testing. Level of evidence: Category 1. [17][18]

6. Clinical decision algorithm (NCCN/ASCO)

• Stage confirmation: Use AJCC 8th‑edition criteria to verify stage IIIB disease. 16
• Node assessment: Evaluate resectability and presence of clinically positive nodal disease. 17
• Adjuvant choice for occult nodal disease (identified by sentinel‑node biopsy): Offer standard adjuvant pembrolizumab or nivolumab. Level of evidence: Category 1. [16][17]
• BRAF testing: Perform BRAF V600E/K mutation analysis, although results do not dictate anti‑PD‑1 selection. 18
• Agent selection between pembrolizumab and nivolumab: Both have comparable efficacy and safety; choice may be based on drug availability and patient preference for dosing frequency. Level of evidence: Category 1. [16][17]
• Treatment duration: Continue the chosen anti‑PD‑1 agent for a total of 12 months (approximately 18 doses) unless disease recurrence, unacceptable toxicity, or patient withdrawal occurs. Level of evidence: Category 1. 16

7. Safety monitoring

• Vigilantly monitor for immune‑related adverse events—including colitis, endocrine disorders, and pneumonitis—as they may arise late in the treatment course. Level of evidence: Category 1. 17

All facts are derived from cited sources (16, 17, 18) and reflect NCCN/ASCO guideline recommendations where indicated.