What is the evidence for neoadjuvant immunotherapy, including checkpoint inhibitors such as pembrolizumab (pembrolizumab) or nivolumab (nivolumab), in the treatment of melanoma?

Neoadjuvant Immunotherapy for Melanoma: Evidence and Recommendations

Neoadjuvant pembrolizumab followed by adjuvant pembrolizumab should be offered to patients with resectable stage IIIB-IV melanoma as it significantly improves event-free survival compared to adjuvant therapy alone. 1

Evidence for Neoadjuvant Immunotherapy in Melanoma

Pembrolizumab (Preferred Regimen)

The strongest evidence comes from the SWOG S1801 randomized phase II trial, which demonstrated:

• 313 patients with resectable stage IIIB-IVC melanoma received either:

  • Neoadjuvant pembrolizumab (3 doses of 200mg every 3 weeks) followed by surgery and adjuvant pembrolizumab (15 doses)
  • Surgery followed by adjuvant-only pembrolizumab (18 doses)

• Results at median follow-up of 14.7 months:

  • Event-free survival at 2 years: 72% in neoadjuvant-adjuvant group vs 49% in adjuvant-only group
  • Similar safety profile: Grade ≥3 treatment-related adverse events in 12% of neoadjuvant-adjuvant group vs 14% in adjuvant-only group 1, 2

Based on these compelling results, both NCCN and ASCO guidelines recommend pembrolizumab as a category 2A, preferred neoadjuvant regimen for resectable stage III melanoma with clinically positive nodes or in-transit metastases 1.

Nivolumab + Ipilimumab (Alternative Regimen)

The "flip-dose" combination of nivolumab 3 mg/kg and ipilimumab 1 mg/kg is recommended as an alternative regimen based on:

• OpACIN-neo trial showed that this dosing schedule provided:
  • Better toxicity profile than standard dosing (20% grade 3-4 immune-related adverse events vs 40-50% with other dosing schedules)
  • Maintained pathologic response rates 1

The original OpACIN study using standard dosing (nivolumab 1 mg/kg + ipilimumab 3 mg/kg) showed high pathologic response rates (78%) but excessive toxicity (90% grade 3-4 adverse events), making this dosing schedule unsuitable 1.

Other Recommended Regimens

NCCN guidelines also include:

• Nivolumab monotherapy
• Nivolumab + relatlimab
• Dabrafenib + trametinib (for BRAF-mutant melanoma)
• Talimogene laherparepvec (T-VEC) for in-transit metastases 1

Mechanism and Rationale

The scientific rationale for neoadjuvant immunotherapy is compelling:

1. Enhanced T-cell response: Administering checkpoint inhibitors before surgery activates tumor-infiltrating T cells while the tumor is still present, generating a stronger systemic immune response 1, 3

2. Preservation of tumor-reactive T cells: In the adjuvant setting, surgical removal of the tumor also removes many potential antitumor T cells that would respond to checkpoint inhibition 1

3. Response assessment: The pathologic and radiographic response to neoadjuvant therapy provides valuable prognostic information that can guide subsequent treatment decisions 1

4. Earlier systemic therapy: Allows for earlier treatment of potential micrometastatic disease 1

Clinical Implications and Algorithm

For patients with resectable stage III (clinically positive nodes) or stage III (satellite/in-transit metastases):

1. First choice: Neoadjuvant pembrolizumab (200mg IV every 3 weeks for 3 doses) followed by surgery and adjuvant pembrolizumab (15 additional doses) 1

2. Alternative regimen (especially if higher response rate is desired despite increased toxicity): Neoadjuvant "flip-dose" nivolumab 3 mg/kg + ipilimumab 1 mg/kg (2 cycles) followed by surgery and adjuvant therapy 1

3. For BRAF-mutant melanoma: Consider either immunotherapy options above or dabrafenib + trametinib 1, 4

Important Considerations and Pitfalls

• Patient selection: Ensure patients have resectable disease before initiating neoadjuvant therapy

• Timing of surgery: Plan for surgical resection after completing the neoadjuvant course (typically after 9 weeks for pembrolizumab)

• Toxicity management: Be prepared to manage immune-related adverse events that may delay surgery (though rates are similar to adjuvant therapy)

• Response assessment: Use both radiographic and pathologic assessment to evaluate response

• Special populations: Limited data exists for mucosal melanoma, though small studies suggest feasibility with response rates of 47% and acceptable safety profiles 5

Emerging Evidence

Recent evidence suggests that neoadjuvant immunotherapy may be superior to the traditional approach of upfront surgery followed by adjuvant therapy for resectable stage III melanoma 6. The NCCN guidelines now state that "neoadjuvant therapy for clinically positive nodes/nodal recurrence is generally preferred over the previous standard approach of therapeutic lymph node dissection (TLND), followed by adjuvant systemic treatment" 1.

This paradigm shift represents a significant advancement in melanoma management, with potential for improved long-term outcomes by leveraging the intact tumor microenvironment to generate more effective antitumor immunity.