What are the treatment options for stage 4 (four) melanoma?

From the Guidelines

For patients with stage 4 melanoma, the most effective treatment approach is adjuvant therapy with nivolumab, which has been shown to improve relapse-free survival (RFS) and should be considered the preferred adjuvant therapy approach. This recommendation is based on the results of the CheckMate 238 trial, which compared adjuvant nivolumab to adjuvant high-dose ipilimumab in patients with resected stage IV melanoma, and found a significant benefit in favor of nivolumab for patients with M1a or M1b disease 1.

Key Considerations

• For patients with resected stage IV melanoma, adjuvant therapy with nivolumab is the preferred approach, with a clear advantage in terms of RFS compared to ipilimumab or placebo 1.
• For patients with BRAF mutations, there is no prospective clinical trial involving BRAF or BRAF/MEK inhibition in the adjuvant setting, but subset analyses of RFS from the COMBI-AD trial suggest similar treatment benefit regardless of stage III disease substage, nodal metastatic burden, and ulceration 1.
• The use of adjuvant therapy in patients with resected stage IV melanoma is supported by recent guidelines, including the 2023 ASCO guideline update, which recommends adjuvant nivolumab or pembrolizumab for stage IIB-C disease and adjuvant nivolumab plus ipilimumab as a potential option for stage IV disease 1.

Treatment Approach

• Immunotherapy with checkpoint inhibitors such as nivolumab or pembrolizumab is a key component of treatment for stage 4 melanoma.
• Targeted therapy combinations like dabrafenib plus trametinib may be used for patients with BRAF mutations.
• Local treatments such as surgery, radiation therapy, or intralesional therapy may be used alongside systemic treatments to address specific problematic metastases.
• Clinical trials exploring new treatment approaches should also be considered.

From the FDA Drug Label

TECENTRIQ, in combination with cobimetinib and vemurafenib, is indicated for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma The treatment for Stage 4 melanoma with BRAF V600 mutation is atezolizumab (TECENTRIQ) in combination with cobimetinib and vemurafenib.

• The recommended dosage of TECENTRIQ is 840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks.
• TECENTRIQ should be administered with cobimetinib 60 mg orally once daily (21 days on and 7 days off) and vemurafenib 720 mg orally twice daily 2.

From the Research

Stage 4 Melanoma Treatment Options

• Immunotherapy has shown promise in treating stage 4 melanoma, with studies demonstrating improved overall survival and progression-free survival rates 3, 4, 5, 6.
• Combination therapies, such as nivolumab plus ipilimumab, have been shown to be effective in treating advanced melanoma, with median overall survival rates of up to 72.1 months 4.
• Monoclonal antibodies directed at programmed cell death protein 1 receptor (PD-1) and its ligand (PDL-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and lymphocyte-activation gene 3 (LAG-3) have provided robust activation of the adaptive immune system, restoring immune surveillance leading to host tumor recognition and destruction 6.

Efficacy and Safety of Treatment Options

• A real-world study comparing the efficacy and safety of nivolumab to ipilimumab + nivolumab as first-line treatment for metastatic melanoma found that overall survival at 36 months was higher in the ipilimumab + nivolumab group (57.1%) than in the nivolumab group (46.6%) 7.
• Progression-free survival at 36 months was significantly improved in the ipilimumab + nivolumab group (42.3%) compared to the nivolumab group (21.9%) 7.
• The overall incidence of side effects was comparable between the two groups, and severe toxicity (grade ≥ 3) was more frequent in the ipilimumab + nivolumab arm (41% vs. 29%) 7.

Future Directions

• Ongoing research is focused on developing novel immunotherapy treatments, including oncolytic virus therapy, and modulators of the tumor microenvironment 5, 6.
• Multiple other immunomodulatory therapeutics are under investigation to overcome resistance to ICI therapy, including the toll-like receptor-9 (TLR-9) and 7/8 (TLR-7/8) agonists, stimulator of interferon genes (STING) agonists, and fecal microbiota transplantation 6.