What are the adjuvant therapy options for stage 3 melanoma?

From the Guidelines

For patients with resected stage III melanoma, the recommended adjuvant therapy options are nivolumab or pembrolizumab for 52 weeks, as these treatments have been shown to significantly reduce recurrence risk. The decision between these options should be individualized based on the patient's BRAF mutation status and other factors, such as the extent of lymph node involvement and overall health.

Key Considerations

• For BRAF-mutated melanoma, options include the combination of dabrafenib and trametinib for 52 weeks, in addition to nivolumab or pembrolizumab 1.
• Patients with stage III disease and microscopic sentinel nodal metastasis <1 mm in diameter were not included in the randomized trials that studied the efficacy of immune checkpoint inhibitors as adjuvant therapy for melanoma, and therefore treatment should be individualized after discussing the risk-benefit quotient with these patients 1.
• Nivolumab and pembrolizumab are FDA-approved adjuvant treatments for patients with melanoma with lymph node involvement who have undergone complete resection of their disease 1.

Treatment Details

• Nivolumab can be administered at a dose of 240 mg every 2 weeks or 480 mg every 4 weeks 1.
• Pembrolizumab can be administered at a dose of 200 mg every 3 weeks or 400 mg every 6 weeks 1.
• Dabrafenib and trametinib can be administered at doses of 150 mg twice daily and 2 mg once daily, respectively, for 52 weeks 1.

Monitoring and Side Effect Management

• Regular monitoring includes clinical examinations every 3 months for the first 2 years, then every 3-6 months for years 3-5, along with imaging studies 1.
• Side effect management is crucial, with immune-related adverse events requiring prompt intervention, sometimes with corticosteroids 1.

From the FDA Drug Label

Adjuvant Treatment of Resected Stage IIB or IIC Melanoma Among the 969 patients with Stage IIB or IIC melanoma enrolled in KEYNOTE-716 [see Clinical Studies (14. 1)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 9.9 months (range: 0 to 15. 4 months). Adjuvant Treatment of Stage III Resected Melanoma The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-054, a randomized (1:1) double-blind trial in which 1019 patients with completely resected Stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=509) or placebo (n=502) for up to one year [see Clinical Studies (14. 1)].

1. • Adjuvant treatment of adult patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy. (1.2)

The adjuvant therapy options for stage 3 melanoma are:

• Pembrolizumab (KEYTRUDA): 200 mg every 3 weeks for up to one year 2
• Ipilimumab (YERVOY): 3 mg/kg every 3 weeks for 4 doses, followed by 3 mg/kg every 12 weeks for up to 4 additional doses 3

From the Research

Adjuvant Therapy Options for Stage 3 Melanoma

The following adjuvant therapy options are available for stage 3 melanoma:

• Anti-programmed cell death protein 1 (PD-1) monotherapy, such as nivolumab and pembrolizumab 4
• BRAF/MEK inhibitors, such as dabrafenib and trametinib, for patients with BRAF V600 mutations 4, 5
• Combination therapy with ipilimumab and nivolumab, which has shown promising efficacy in a phase II clinical trial 4

Recurrence-Free Survival Rates

The recurrence-free survival rates for stage 3 melanoma patients treated with adjuvant therapy are:

• Nivolumab: 72% and 65% at 2 and 3 years, respectively, for stage IIIB melanoma, and 60% and 53.5% at 2 and 3 years, respectively, for stage IIIC melanoma 4
• Pembrolizumab: 70% and 65.7% at 2 and 3 years, respectively, for stage IIIB melanoma, and 60% and 54.3% at 2 and 3 years, respectively, for stage IIIC melanoma 4
• Dabrafenib/trametinib: 68% and 60% at 2 and 3 years, respectively, for stage IIIB melanoma, and 59% and 47% at 2 and 3 years, respectively, for stage IIIC melanoma 4

Real-World Clinical Outcomes

Real-world clinical outcomes for stage 3 melanoma patients treated with adjuvant therapy have been reported in several studies:

• A retrospective analysis of 113 patients treated with anti-PD-1 therapy or dabrafenib/trametinib reported a median recurrence-free survival of 12 and 24 months of 81% and 64%, respectively 6
• A single-centre retrospective clinical practice review of 110 patients treated with pembrolizumab or nivolumab reported a 12-month recurrence-free survival of 78.9% and 86.7%, respectively, and a 24-month recurrence-free survival of 77.6% and 80%, respectively 7

Factors Influencing Adjuvant Therapy Recommendations

The following factors influence adjuvant therapy recommendations for stage 3 melanoma:

• Melanoma sub-stage and individual patient's therapy risk/benefit profile 8
• Uncertainty about adjuvant immunotherapy's effectiveness and views about treatment burden patients might consider acceptable 8
• Patient's disease sub-stage and treatment risk versus benefit 8