EADV 2024 Congress: New perspectives on melanoma

Diagnostic approaches in adults

The current gold standard for diagnosing melanoma remains full-body skin examinations and dermoscopy, an advanced method that improves the sensitivity and specificity of clinical diagnosis. Digital dermoscopy has also gained prominence, allowing for image storage and follow-up of suspicious lesions over time.

For lesions suspicious of melanoma, excisional biopsy with 1-3 mm margins is recommended, followed by histopathological analysis. Key features include asymmetry, irregular borders, color variation, and diameter >6 mm (ABCDE criteria).

Molecular testing for mutations in genes like BRAF, NRAS, and KIT is also becoming more common, particularly for advanced stages, as it helps guide targeted therapies. Reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) are non-invasive imaging technologies increasingly used in specialized centers, allowing for the analysis of cellular structures within the skin without the need for biopsy.

Diagnostic challenges in pediatric melanoma

Pediatric melanoma is much rarer, accounting for less than 2% of melanoma cases. However, its diagnosis can be particularly challenging because clinical presentation often differs from that in adults. Lesions in children are often amelanotic or nodular, leading to misdiagnosis as benign conditions such as Spitz nevi.

The diagnostic approach for pediatric patients relies heavily on dermoscopy, which helps differentiate melanomas from benign lesions. Excisional biopsy remains essential for confirmation. Genetic testing for germline mutations, such as in the CDKN2A and BAP1 genes, may be indicated for children with a family history of melanoma.

Treatment of adult melanoma

The European Society for Medical Oncology (ESMO) and the European Dermatology Forum (EDF) provide clear guidelines for managing melanoma, depending on its stage.

Stage I-II (Early Melanoma): surgical excision remains the cornerstone of treatment. A wide excision margin of 1-2 cm is recommended, depending on tumor thickness. Sentinel lymph node biopsy is considered for melanomas >1 mm in thickness or with other high-risk features.

Stage III (Locally Advanced): patients with sentinel lymph node metastasis are typically managed with surgical excision of lymph nodes. Adjuvant therapies, such as anti-PD-1 immunotherapy (nivolumab or pembrolizumab) or BRAF/MEK inhibitors for BRAF-mutated tumors, are recommended to reduce the risk of recurrence.

Stage IV (Metastatic): for metastatic melanoma, immunotherapy with anti-PD-1/anti-CTLA-4 antibodies (nivolumab and ipilimumab) has become the gold standard due to their ability to produce durable responses. Targeted therapy with BRAF and MEK inhibitors (dabrafenib/trametinib) is used for patients with BRAF-mutated melanomas. European guidelines recommend these therapies as first-line treatment options, tailored based on the patient's molecular profile and overall health.

Treatment of pediatric melanoma

Therapeutic approaches to pediatric melanoma largely mirror those for adults, though clinical data is more limited due to its rarity. Surgery remains the mainstay of treatment, with wide local excision and sentinel lymph node biopsy in select cases.

For advanced pediatric melanoma, immunotherapy (e.g., pembrolizumab) has been shown to be effective, though pediatric-specific trials are still ongoing. In Europe, children with advanced melanoma are often enrolled in clinical trials to access novel therapies. Genetic counseling and close surveillance are crucial, especially for those with familial cancer syndromes.

The importance of early diagnosis and treatment of melanoma

Early diagnosis is essential to increase the chances of survival: patients diagnosed with melanomas at an early stage have a five-year survival rate of more than 90%. The EADV 2024 congress provided a platform to discuss innovations in the field, presenting new approaches to improve the management of this disease.

During the congress, a major study highlighted the emerging role of circulating tumor biomarkers for the diagnosis of melanoma in its early stages. One of the main studies presented demonstrated how circulating tumor antigens (CTAg), including MART-1 and GP100, can be used to detect stage I and II melanomas with high sensitivity (98%) and specificity (76%).

In parallel, a session on the use of artificial intelligence (AI) for improving diagnosis illustrated how machine learning-based algorithms are capable of analyzing dermoscopic images, often outperforming dermatologists in diagnostic accuracy. The introduction of AI systems into clinical practice can offer support to specialists, reducing the risk of missed diagnoses.

Pediatric melanoma: biological differences and diagnostic difficulties

Pediatric melanoma, although rare, represents a unique challenge, with an estimated annual incidence of about 1% of all pediatric cancers. A retrospective study highlighted the biological differences between pediatric and adult melanomas. In children, a higher prevalence of mutations in the BRAF gene was observed, present in approximately 50-60% of cases. However, NRAS mutations, common in adults, are less frequent in pediatric patients.

It was also discussed how the use of dermoscopy in pediatric patients can significantly improve diagnostic accuracy. Melanomas in children can mimic benign conditions, making early diagnosis particularly complex. The congress highlighted the importance of advanced diagnostic tools to distinguish between benign and malignant lesions.

Innovative treatments for advanced melanoma

The focus was also on novel treatments for advanced or resistant melanomas. JAK inhibitors have emerged as promising modulators of the immune response in patients with metastatic melanoma. The drug povorcitinib, a selective JAK1 inhibitor, showed promising results in preclinical and phase 2 studies, with reduction of tumor growth and clinical improvements in patients with advanced melanoma.

Another point of interest was the combination of immunotherapy therapies. Preliminary study results on nivolumab and ipilimumab showed an increased overall response rate in patients with metastatic melanoma, with improved progression-free survival compared to single therapies.

New strategies to overcome treatment resistance

One of the most significant challenges in the treatment of advanced melanoma is resistance to standard treatments such as BRAF and MEK inhibitors. New data presented at EADV suggested that the addition of combination therapies, such as the use of BET protein inhibitors together with BRAF/MEK inhibitors, could slow disease progression. Preclinical studies have shown a reduction in tumor cell proliferative activity in resistant melanoma models, with promising implications for future clinical trials.

Advantages of neoadjuvant therapy

Neoadjuvant therapy, administered before surgical resection, has shown multiple advantages in melanoma treatment. As highlighted by Prof. Christian Blank (Amsterdam, Netherlands), one key benefit is the "priming of a more potent immune response while the primary tumor is still present. The tumor acts as a “natural vaccine” presenting antigens that help activate tumor-specific T cells. This improves the immune system’s ability to eradicate micrometastatic disease, enhancing long-term outcomes.

Clinical studies, including the OpACIN trial, demonstrated that neoadjuvant immunotherapy, particularly the combination of anti-CTLA-4 (ipilimumab) and anti-PD-1 (nivolumab), significantly increased event-free survival (EFS) compared to standard adjuvant therapies. By delivering treatment preoperatively, the therapy may also reduce the risk of systemic relapse.

Optimizing dosing and reducing toxicity: OpACIN and OpACIN-neo

In the original OpACIN trial, combining ipilimumab and nivolumab resulted in remarkable efficacy but also considerable toxicity, with grade 3/4 adverse events affecting nearly 50% of patients. This prompted the design of the OpACIN-neo trial, which explored lower doses of ipilimumab to mitigate these side effects. By reducing the dose, the trial achieved a substantial decrease in severe toxicities (down to 20%) while maintaining high response rates.

These results were pivotal, as the regimen demonstrated a pathological complete response rate of 60%, and EFS outcomes in neoadjuvant settings showed improved disease control compared to the traditional post-surgical adjuvant approach.

Surgical implications and PRADO Trial

The PRADO trial introduced a surgical refinement that reduces the extent of lymph node dissection in patients with melanoma. Following neoadjuvant immunotherapy, patients with a major pathological response (MPR) were shown to benefit from less invasive surgery, as complete lymphadenectomy could often be avoided.

Patients who achieved an MPR or a complete pathological response after neoadjuvant treatment had excellent outcomes without the need for further aggressive surgery. This approach not only improves quality of life but also reduces the risks associated with extensive nodal resections, such as lymphedema.

Biomarkers and personalized neoadjuvant strategies

Another critical focus in neoadjuvant therapy is the identification of predictive biomarkers to tailor treatment. Biomarkers such as the tumor mutational burden (TMB) and interferon-gamma gene signatures are proving useful in predicting patient responses to checkpoint inhibitors.

Patients with high interferon-gamma signatures are more likely to respond to anti-PD-1 monotherapy (e.g., nivolumab or pembrolizumab). Conversely, those with lower expression levels may require combination therapy (ipilimumab + nivolumab) to achieve a sufficient immune response. This strategy helps in personalizing therapy, aiming for higher efficacy while minimizing unnecessary toxicity.

Exploration in stage II melanoma

Looking ahead, Blank discussed ongoing trials that are investigating the role of neoadjuvant therapy in patients with “Stage II melanoma”. Although neoadjuvant treatment has traditionally been used in patients with Stage III/IV disease, recent evidence suggests that early intervention with immunotherapy might also improve outcomes in patients with lower-stage disease, potentially reducing recurrence risk and improving overall survival rates.

Management of toxicities

The management of immune-related adverse events (irAEs) remains a central challenge in neoadjuvant therapy. As seen in OpACIN-neo, reducing the ipilimumab dose was a successful strategy in limiting the frequency and severity of toxicities without compromising efficacy. Ongoing research is focused on balancing therapeutic benefits with the risk of immune-related toxicities, ensuring that treatment is not only effective but also tolerable for a broader patient population.