What Is the Best Treatment for Stage 3 Malignant Melanoma?

What Is Stage 3 Malignant Melanoma?

Stage 3 (stage III) malignant melanoma is a stage in which the cancer has spread to lymph nodes but has not yet formed metastases in distant organs. At this stage, patients face a high risk of recurrence or metastasis after surgery, the main treatment, and early intervention can bring the disease under control.

New Approaches: A Critical Challenge

Today, conventional surgery is only the first step in treating stage 3 malignant melanoma, and the need for advanced strategies to complement treatment is growing. Given the possibility of cancer recurring from microscopic residual cells, new treatments have the potential to change the course of the disease. Among genetic characteristics, BRAF mutations occur in 40% of patients and stand out as a critical factor influencing treatment decisions. The presence of this mutation allows treatment strategies to be individualized and increases the effectiveness of targeted treatment options.

Adjuvant and Neoadjuvant Treatments

In this context, neoadjuvant and adjuvant treatments, given before or after surgery, are important approaches aimed at minimizing patients' risk of cancer recurrence and improving survival. The findings of important studies of these strategies, such as NADINA and COMBI-AD, are examined below.

Neoadjuvant Immunotherapy Study: Nivolumab and Ipilimumab

In the NADINA study, patients with stage III malignant melanoma received a combination of neoadjuvant nivolumab and ipilimumab before surgery. In this study, 423 patients received two cycles of ipilimumab (80 mg) and nivolumab (240 mg). After approximately 10 months of follow-up, the neoadjuvant treatment group achieved longer disease-free survival than the group receiving adjuvant treatment after surgery.

Findings:

• Disease-Free Survival: At the end of a median follow-up of 9.9 months, the neoadjuvant group's 12-month disease-free survival rate was  83.7% , compared with  57.2%  in the adjuvant group (a difference of 26.5%). This shows that neoadjuvant treatment significantly reduced the risk of disease recurrence, progression, or death.
• Pathological Response: In the neoadjuvant group, 59% of patients had substantial tumor regression after surgery (a major pathological response), 8% had a partial response, and 26.4% had no response.
• Recurrence-Free Survival: In the neoadjuvant group, the 12-month recurrence-free survival rate was 95.1% in patients with substantial tumor regression, 76.1% in those with a partial response, and 57% in those with no response.
• Adverse Effects: Grade 3 or higher adverse effects were more frequent in the neoadjuvant group (29.7%) than in the adjuvant group (14.7%). However, these adverse effects did not cause surgical complications.

Below,  the disease-free survival data, the primary endpoint of the NADINA study, can be seen:

Study of Adjuvant Dabrafenib and Trametinib in Patients with a BRAF V600E Mutation

For patients with stage III melanoma positive for a BRAF V600E mutation, adjuvant treatment with dabrafenib and trametinib was given in the COMBI-AD study .

Based on this study, in April 2018 this combination anti-BRAF treatment for adjuvant melanoma therapy received FDA approval.

In the study, 870 patients received either the combination of dabrafenib (150 mg) and trametinib (2 mg) or placebo for 12 months.

The study's long-term survival results were published in June 2024 in NEJM :

• Survival Results: At eight years of follow-up, the group receiving dabrafenib and trametinib had a survival rate of 71%, compared with 65% in the placebo group. However, this difference did not reach statistical significance.
• Adverse Effects: Serious adverse effects were more frequent in patients receiving dabrafenib and trametinib (41%) than in the placebo group (13%).
• BRAF V600E-Positive Patients: In this subgroup, treatment was found to reduce the risk of death by 25%, but the same effect was not observed in patients with a BRAF V600K mutation.

Based on these results, the combination of dabrafenib and trametinib was reported to provide limited long-term benefit in patients with BRAF V600E and not to substantially improve overall survival.

Conclusion and Recommendations

According to the data, while adjuvant BRAF/MEK inhibitors offer limited benefits in treating stage III malignant melanoma, particularly in patients with a BRAF V600E mutation, neoadjuvant combination immunotherapy may be a more effective option for all patients with stage III melanoma. Because the pathological responses achieved with neoadjuvant immunotherapy have the potential to improve long-term survival, this treatment approach is recommended as the standard treatment for all patients with stage III malignant melanoma.