A 58-year-old man presents with a 2.5 cm dark nodular lesion on his back with irregular borders, present for 8 months. Dermoscopy shows asymmetry, multiple colors, and ulceration. Excision biopsy confirms cutaneous melanoma, Clark level IV, Breslow thickness 3.2 mm, with 2 mitoses per mm². Sentinel lymph node biopsy is negative. Which is the drug of choice for adjuvant therapy in this patient?

## Adjuvant Therapy for High-Risk Melanoma **Key Point:** Nivolumab (anti-PD-1 checkpoint inhibitor) is now the preferred adjuvant agent for resected stage III melanoma (node-positive) and high-risk stage IIB/IIC melanoma (Breslow ≥1 mm with ulceration or high mitotic rate). ### Rationale for This Patient This patient has: - Breslow thickness 3.2 mm (>1 mm = high risk) - Ulceration present (poor prognostic factor) - High mitotic rate (2/mm²) - Negative sentinel lymph node (stage IIB/IIC) These features qualify him for adjuvant immunotherapy. ### Evidence Base **High-Yield:** The CheckMate 238 trial demonstrated that nivolumab significantly improved recurrence-free survival (RFS) compared to interferon-alpha in resected stage IIIB/IIIC melanoma. This led to FDA approval and now represents the standard of care. ### Comparison of Adjuvant Options | Agent | Mechanism | Indication | RFS Benefit | Toxicity Profile | |-------|-----------|-----------|-------------|------------------| | **Nivolumab** | Anti-PD-1 | Stage IIB–IIIC | Superior (CheckMate 238) | Immune-related adverse events (irAEs) | | **Interferon-alpha** | Immunostimulant | Stage IIB–IIIC | Modest (historical) | Flu-like, hepatotoxicity, depression | | **Dacarbazine** | Alkylating agent | Metastatic disease | Not for adjuvant | Myelosuppression, nausea | | **Temozolomide** | Alkylating agent | Metastatic disease | Not for adjuvant | CNS penetration, myelosuppression | ### Clinical Pearl **Nivolumab dosing:** 3 mg/kg IV every 2 weeks for up to 1 year in the adjuvant setting. Monitor for immune checkpoint inhibitor-related toxicities (colitis, pneumonitis, hepatitis, endocrinopathy). ### Treatment Algorithm ```mermaid flowchart TD A[Resected Cutaneous Melanoma]:::outcome --> B{Breslow Thickness & Stage?}:::decision B -->|<1 mm, no ulceration| C[Observation]:::action B -->|≥1 mm OR ulceration| D{Node-positive?}:::decision D -->|Yes - Stage IIIB/C| E[Nivolumab or Pembrolizumab]:::action D -->|No - Stage IIB/C| F[Nivolumab preferred]:::action E --> G[1-year adjuvant course]:::action F --> G G --> H[Surveillance imaging & follow-up]:::outcome ``` **Warning:** Dacarbazine and temozolomide are reserved for metastatic disease, not adjuvant therapy. Interferon-alpha is now rarely used given superior efficacy and tolerability of checkpoint inhibitors.