Is neoadjuvant immunotherapy (immunotherapy given before the main treatment) effective for treating melanoma (skin cancer)?

Neoadjuvant Immunotherapy in Melanoma: Current Evidence and Recommendations

Based on current evidence, neoadjuvant immunotherapy for melanoma shows promise but is not yet recommended as standard of care outside clinical trials, with the exception of neoadjuvant pembrolizumab which has demonstrated significant event-free survival benefit in resectable stage III-IV melanoma.

Current Guideline Recommendations

The most recent guidelines provide clear direction regarding neoadjuvant therapy for melanoma:

• The 2023 ASCO guideline update now recommends neoadjuvant pembrolizumab (three courses of 200 mg every 3 weeks) followed by resection and adjuvant pembrolizumab for patients with clinical stage III-IV resectable melanoma 1.

• Prior to this update, the 2020 ASCO guideline made no recommendation for or against routine use of neoadjuvant therapy for resectable melanoma, instead encouraging enrollment in clinical trials 1.

• The NCCN guidelines (2019-2024) consistently state there are insufficient data to recommend any specific agent as neoadjuvant therapy for melanoma outside clinical trials 1.

Evidence for Neoadjuvant Immunotherapy

Pembrolizumab (Anti-PD-1)

The SWOG S1801 trial provided the strongest evidence supporting neoadjuvant immunotherapy, showing:

• Improved event-free survival with neoadjuvant pembrolizumab followed by adjuvant therapy compared to adjuvant therapy alone
• 23% fewer events at 2 years in the neoadjuvant arm
• Same total number of pembrolizumab cycles (18) in both arms, just different timing 1

Ipilimumab plus Nivolumab Combination

Recent studies show:

• High response rates (RECIST ORR 73%, pathologic complete response 45%)
• Substantial toxicity (73% grade 3 treatment-related adverse events) 2
• The NADINA trial (2024) demonstrated significantly improved event-free survival with neoadjuvant ipilimumab plus nivolumab followed by surgery compared to surgery followed by adjuvant nivolumab 3

BRAF/MEK Inhibitors

For BRAF V600 mutation-positive melanoma:

• A small trial of neoadjuvant dabrafenib plus trametinib showed significantly improved event-free survival compared to upfront surgery 1
• The NCCN recommends considering dabrafenib/trametinib as a category 2A neoadjuvant option for resectable stage III melanoma when immunotherapy is contraindicated 1

Talimogene Laherparepvec (T-VEC)

• Improved recurrence-free survival and overall survival compared to surgery alone
• Recommended only for certain patients with satellite/in-transit disease 1

Practical Approach to Neoadjuvant Therapy

1. Patient Selection:

   • Resectable clinical stage III (clinically positive nodes) or stage IV melanoma
   • Good performance status
   • No contraindications to immunotherapy

2. Preferred Treatment Options:

   • First choice: Neoadjuvant pembrolizumab (three cycles of 200 mg every 3 weeks) followed by surgery and adjuvant pembrolizumab (15 cycles) 1
   • For BRAF V600-mutated melanoma if immunotherapy contraindicated: Consider dabrafenib plus trametinib for 4-12 weeks preoperatively 1

3. Monitoring and Response Assessment:

   • Pathologic response correlates with long-term outcomes
   • Patients with major pathologic response (<10% viable tumor) or complete pathologic response have better survival outcomes 4

Important Considerations and Limitations

• Toxicity management: Neoadjuvant immunotherapy, particularly combination therapy, can cause significant immune-related adverse events requiring prompt recognition and management

• Limited long-term data: While 5-year follow-up data exists for some small trials 4, larger studies with longer follow-up are needed

• Cochrane review caution: A 2023 systematic review concluded there is insufficient evidence to support routine use of neoadjuvant treatment in clinical practice outside trials 5

• Ongoing research: Multiple clinical trials are investigating various neoadjuvant approaches, which may further refine recommendations

Conclusion

The landscape of neoadjuvant therapy for melanoma is evolving rapidly. While the Swedish study your colleague mentioned may have shown limitations of neoadjuvant immunotherapy, the most recent high-quality evidence, particularly from the SWOG S1801 trial, supports the use of neoadjuvant pembrolizumab in resectable stage III-IV melanoma. For patients who don't qualify for this approach or have contraindications, clinical trial enrollment should be considered when available.