What were the eligibility criteria, dosing regimen, and primary outcomes of the SWOG S1801 trial evaluating neoadjuvant pembrolizumab (Keytruda) for resectable stage III (IIIB–IIIC) or oligometastatic stage IV cutaneous melanoma?

SWOG S1801 Trial: Neoadjuvant Pembrolizumab for Melanoma

The SWOG S1801 trial enrolled patients with resectable stage IIIB-IVC cutaneous, acral, and mucosal melanoma, administered 3 doses of neoadjuvant pembrolizumab (200 mg IV every 3 weeks) followed by surgery and 15 additional doses of adjuvant pembrolizumab, demonstrating a 23% absolute improvement in 2-year event-free survival (72% vs 49%) compared to adjuvant-only pembrolizumab. 1

Eligibility Criteria

The trial included patients with the following characteristics:

• Stage IIIB-IVC melanoma that was clinically detectable, measurable, and amenable to complete surgical resection 1, 2
• Melanoma subtypes included cutaneous, acral, and mucosal melanomas 1
• Resectable disease with clinically positive lymph nodes or oligometastatic stage IV disease 1
• Only 23 patients with stage IV disease were included in the trial, representing a small subset of the total enrollment 1

Dosing Regimen

The neoadjuvant-adjuvant arm received:

• Neoadjuvant phase: Pembrolizumab 200 mg IV every 3 weeks for a maximum of 3 doses (approximately 9 weeks) 1
• Surgical resection: Performed 3-6 weeks after completing neoadjuvant therapy 3
• Adjuvant phase: Pembrolizumab 200 mg IV every 3 weeks for 15 additional doses 1
• Total treatment duration: 18 doses over approximately 1 year 1, 2

The control arm received surgery followed by 18 doses of adjuvant pembrolizumab alone, ensuring both groups received identical total pembrolizumab exposure 1

Primary Outcomes and Results

Event-Free Survival (Primary Endpoint)

The trial defined events comprehensively as: disease progression or toxicity precluding surgery, inability to achieve complete resection, complications preventing adjuvant therapy initiation within 84 days post-surgery, melanoma recurrence, or death from any cause 2

At median follow-up of 14.7 months:

• 2-year EFS: 72% (95% CI, 64-80%) in neoadjuvant-adjuvant arm vs 49% (95% CI, 41-59%) in adjuvant-only arm 1
• Absolute difference: 23% improvement (95% CI, 11-35%) 1
• Statistical significance: P = 0.004 by log-rank test 2

Safety Profile

The toxicity profile was remarkably favorable:

• Grade ≥3 treatment-related adverse events: 12% in neoadjuvant-adjuvant arm vs 14% in adjuvant-only arm 1
• No grade 3-4 immune-related adverse events precluded surgery in the neoadjuvant arm 4
• No new toxic effects were identified with the neoadjuvant approach 2

Clinical Implementation Based on Guidelines

ASCO 2023 Guideline Recommendations

ASCO now strongly recommends neoadjuvant pembrolizumab (maximum 3 courses of 200 mg every 3 weeks) followed by resection and adjuvant pembrolizumab (maximum 15 courses) for patients with clinical stage IIIB-IV resectable melanoma 1

The Expert Panel emphasized that since all patients received identical total pembrolizumab cycles (a regimen already recommended for adjuvant therapy), there is minimal additional harm from delivering 3 cycles neoadjuvantly 1

NCCN 2024 Guideline Recommendations

NCCN designates pembrolizumab as a Category 2A preferred regimen for neoadjuvant therapy in: 1

• Resectable stage III with clinically positive nodes
• Stage III with clinically satellite/in-transit metastasis
• Local satellite/in-transit recurrence
• Nodal recurrence

Neoadjuvant therapy is now generally preferred over the previous standard approach of therapeutic lymph node dissection followed by adjuvant systemic treatment 1

Important Caveats and Limitations

Methodological Concerns

A critical analysis raises three potential limitations that warrant careful interpretation: 5

• Arbitrary event assignment rules may have affected event distribution over time
• Different rates of early censoring between groups introduce possibility of informative censoring, potentially creating artifactual EFS benefit
• Phase 2 trial design carries inherent risk of chance findings requiring phase 3 confirmation before widespread adoption 5

Evidence Gaps

• Overall survival data not yet reported at the time of primary analysis 1
• Hazard ratios for EFS not provided, only absolute differences at 2 years 1
• Limited stage IV disease representation (only 23 patients), though ASCO Expert Panel believes these patients would benefit despite sparse evidence 1

Pathologic Response as Prognostic Marker

Long-term follow-up data from single-agent neoadjuvant pembrolizumab trials demonstrate that pathologic response strongly predicts outcomes: 6

• Patients with major pathologic response (MPR, <10% viable tumor): 100% 5-year overall survival
• Patients with >10% viable tumor: 72.8% 5-year overall survival
• Median time to recurrence: 3.9 years for MPR vs 0.6 years for non-MPR (P = 0.044) 6

This suggests pathologic response assessment should guide subsequent adjuvant therapy decisions, though the SWOG S1801 protocol mandated continuation of pembrolizumab regardless of pathologic response 3