How New Research Is Redefining Melanoma Treatment

The treatment landscape for melanoma saw significant advancements in 2024, as highlighted by Elisa Funck-Brentano, MD, PhD, from Ambroise-Paré Hospital in Paris, France, during her presentation at the 2024 Dermatology Days of Paris conference in Paris.

Checkpoint Inhibitors in Neoadjuvant Therapy

The standard approach for treating resectable stage III melanoma with locoregional metastases has traditionally involved surgery followed by adjuvant therapy. However, the phase 3 NADINA trial, published in 2024, is driving a paradigm shift. The trial demonstrated that bi-immunotherapy with ipilimumab and nivolumab administered before surgery, followed by tailored adjuvant therapy based on pathologic response, significantly outperformed nivolumab monotherapy in both event-free survival and metastasis-free survival.

“Neoadjuvant therapy provides the added benefit of assessing histological or pathological response by evaluating the percentage of viable tumor cells, with a major pathological response defined as the presence of 10% or less viable tumor cells,” explained Funck-Brentano.

Results from the NADINA trial showed that more than 60% of patients in the bi-immunotherapy arm achieved a major pathologic response, which was strongly associated with improved recurrence-free survival. “Checkpoint inhibitors appear to be more effective when the tumor remains in place,” Funck-Brentano noted. Anti-programmed cell death protein 1 (PD-1) therapies, either alone or in combination with anti-cytotoxic T-lymphocyte–associated antigen 4 therapies, are now considered the new standard in neoadjuvant treatment. However, these therapies have not yet received marketing authorization. Major pathologic response serves as a key factor in determining subsequent adjuvant treatment strategies.

Daromun and Biomarkers

Another promising development in melanoma treatment is daromun, an immunocytokine designed to stimulate antitumor immunity within the tumor microenvironment. Data from a phase 3 trial, presented at the 2024 American Society of Clinical Oncology meeting, demonstrated that intralesional daromun injections in the neoadjuvant setting significantly reduced the risk for recurrence and distant metastases compared with surgery alone.

Research into predictive biomarkers for immunotherapy response is also progressing. Preliminary evidence suggests that circulating tumor DNA positivity after surgery is linked to an increased risk for recurrence. Some studies indicate that emotional stress may suppress the immune response, potentially affecting treatment outcomes. However, while these findings are promising, no biomarker has yet been validated for routine clinical use.

Adjuvant Therapy

Recent long-term data on pembrolizumab and nivolumab has reaffirmed the benefits of anti-PD-1 therapies in managing residual melanoma. However, Funck-Brentano cautioned, “Most patients do not benefit from treatment — either because they would not relapse without it or because they relapse despite treatment.”

For patients with stage IIB or IIC melanoma, surveillance remains a reasonable alternative, as reflected in the therapeutic management algorithm from the French Society of Dermatology’s Skin Cancer Group published in 2024.

In resected stage III melanoma, long-term follow-up has highlighted the efficacy of adjuvant therapies. A 10-year analysis of combined anti-BRAF and anti-MEK therapy (dabrafenib and trametinib) demonstrated a reduction in recurrence and distant metastases risk. However, the 20% reduction in mortality risk was not statistically significant. Similarly, 7-year data for pembrolizumab revealed a metastasis-free survival benefit for a year of treatment, though no significant impact on overall survival was observed.

Encouraging results have also emerged for the messenger RNA (mRNA)–based vaccine mRNA-4157 (V940). This vaccine targets tumor-specific neoantigens absent in normal cells. When combined with pembrolizumab, it improved recurrence-free and metastasis-free survival compared with pembrolizumab monotherapy in patients with high-risk, resected stage III melanoma while maintaining an acceptable safety profile.

New Options for Metastatic Melanoma

First-line treatment for metastatic melanoma continues to focus on immunotherapy. Long-term data from the CheckMate 067 trial confirmed the superiority of nivolumab combined with ipilimumab, as well as nivolumab monotherapy, compared with ipilimumab alone. “After 6 years, 50% of patients are alive, with median melanoma-specific survival exceeding 10 years. This suggests that many patients may die from causes unrelated to melanoma — or, in essence, they are cured,” said Funck-Brentano.

As of January 2024, the combination of nivolumab and relatlimab, an anti-LAG3 agent, has been approved as a first-line treatment for advanced melanoma without brain metastases and with tumor programmed death-ligand 1 expression less than 1%. An indirect comparison with CheckMate 067 data suggested similar efficacy but improved tolerability with this combination, presenting a valuable option for patients.

For patients who progress on anti-PD-1 therapy, the combination of lenvatinib, a multikinase inhibitor, and pembrolizumab has shown promise. Four-year follow-up data from the LEAP-004 trial revealed an overall response rate of 25.2%, increasing to 33.3% in patients previously treated with dual immunotherapy. Although associated with adverse effects, this regimen may be considered off-label for selected cases.

In the United States, tumor-infiltrating lymphocytes received regulatory approval in 2024 for second-line treatment of metastatic melanoma. Ongoing research is exploring their use as a potential first-line therapy.

Emerging evidence suggests that the timing of anti-PD-1 infusion influences efficacy. A meta-analysis found that administering these therapies in the morning, aligning with the immune system’s circadian rhythm, may improve outcomes. However, prospective studies are needed to validate this approach.

Conclusion

Melanoma treatment is advancing rapidly, with significant progress in neoadjuvant and adjuvant therapies and the introduction of new options for metastatic disease. These developments underscore the need for personalized treatment approaches, guided by long-term data and emerging biomarkers, to optimize outcomes for patients with melanoma.

This story was translated fromUnivadis France using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.