Targeted and Immune Therapy

Importance: Melanoma, the fifth most common cancer in the US, has increased from 8.8 per 100 000 in 1975 to 28.42 per 100 000 in 2022. Cutaneous melanoma comprises 94% of cases, with 104 960 US cases projected for 2025.

Observations: Cutaneous melanoma presents as a new, changing, or irregularly pigmented skin lesion. Cutaneous melanoma subtypes include superficial spreading (≈70%), lentigo maligna (≈15%), nodular (≈5%), desmoplastic (≈4%), amelanotic (2%-8%), spitzoid (<2%), and acral (≈1%). Risk factors for cutaneous melanoma include UV radiation exposure, skin type (eg, skin that always burns, never tans), presence of benign and atypical nevi, and personal or family history of melanoma. Primary prevention consists of avoiding direct sunlight and indoor tanning, and photoprotection (sunscreen and sun-protective clothing). Based on United States Cancer Statistics data from 1999 to 2021, 77% of patients with cutaneous melanoma had localized disease (involving only the primary site), 9.5% had regional (nodal) disease, 4.7% had distant metastasis, and 8.8% were unstaged. Melanoma staging, which includes tumor thickness and ulceration and presence of lymph node or distant metastasis, ranges from stage 0 (melanoma in situ) to stage IV (distant metastasis). Localized melanoma (stage IA-IIA) is surgically excised, with margins of 0.5 cm to 2 cm based on depth of invasion. Sentinel lymph node biopsy is recommended for cutaneous melanoma that is ulcerated or 0.8 mm or more thick. Following surgery, patients with stage IIB-C melanoma have improved recurrence-free survival with adjuvant anti-PD-1 immunotherapy compared with placebo (hazard ratio [HR] for recurrence or death, 0.62 [95% CI, 0.49-0.79] for pembrolizumab and 0.42 [95% CI, 0.30-0.59] for nivolumab). For stage III disease, recurrence risk is decreased with nivolumab (HR, 0.72 [95% CI, 0.60-0.86]), pembrolizumab (HR, 0.61 [95% CI, 0.51-0.72]), or BRAF + MEK inhibitor therapy (dabrafenib + trametinib) (HR, 0.52 [95% CI, 0.43-0.63]). First-line treatment for distant metastatic or unresectable melanoma is dual checkpoint blockade with ipilimumab (anti-CTLA-4) and nivolumab. In 2017, 10-year melanoma-specific survival rates were 98% to 94% for stage IA-B, 88% to 75% for stage IIA-C, 88% for stage IIIA, 77% to 60% for stage IIIB-C, and 24% for stage IIID. In 2024, patients with distant metastatic or unresectable melanoma treated with ipilimumab and nivolumab had a 10-year overall survival rate of 43%.

Conclusions and relevance: Melanoma is a common cancer in the US. Treatment for stage IA-IIA melanoma is surgical resection. Anti-PD-1 immunotherapy after surgical excision improves recurrence-free survival in stages IIB-C melanoma. For stage III melanoma, anti-PD-1 immunotherapy or BRAF + MEK inhibitor therapy decreases risk of melanoma recurrence. First-line therapy for metastatic melanoma is dual checkpoint blockade with ipilimumab and nivolumab.