Melanoma is a malignant tumour that arises from the uncontrolled proliferation of melanocytes – pigment-producing cells. While the most common form of melanoma is cutaneous, it can also arise in mucosal surfaces, the uveal tract, and leptomeninges.4

The worldwide incidence of melanoma has risen rapidly over the course of the last 50 years.

The majority of melanomas are diagnosed at an early stage, however, some patients present for medical care at a late stage when the disease has already metastasised. Melanomas are capable of metastasising to both regional and distant sites. The most common sites of regional metastasis are nearby skin, subcutaneous tissue, and lymph nodes.5

Metastases to the skin are referred to as either satellite lesions (if they are relatively close to the primary tumour) or in-transit metastases (if they are relatively more distant), though do not differentially influence melanoma staging.5

Metastasis to the skin may be the first external clue that lymphatic or hematogenous spread has occurred. The most common clinically apparent sites of distant metastases in melanoma patients are: skin, lung, brain, liver, bone, and intestine.5

Increase in melanoma

The worldwide incidence of melanoma has risen rapidly over the course of the last 50 years. Its incidence is greatest among fair-skinned populations and in regions of lower latitude. Incidence is greater among geriatric populations.4

The average age at diagnosis is 57 years, and up to 75% of patients are younger than 70 years of age. Melanoma is notorious for affecting young and middle-aged people, unlike other solid tumours, mainly affecting older adults. De Wet et al found that the mean age of the majority of patients diagnosed with melanoma in South Africa was 65 years.6,7

Symptoms and location of malignant melanoma

Melanomas can develop in or near a previously existing precursor lesion or in healthy-appearing skin. A malignant melanoma developing in healthy skin is said to arise de novo, without evidence of a precursor lesion.7

The location of malignant melanoma lesions depends on environmental, genetic, sociological, and demographical factors. In women, the melanoma lesions seem to appear more often in their lower extremities, while in the case of men such lesions seem to be more often on their torsos.7

In both cases, the difference was statistically significant when the specific locations are considered in women the lesions were more often located on their shins, whereas for men the lesions were located on their backs.7

It has been observed that there is a dependency between lesion localisation and the age of patients. The lesions located on heads and necks were most common in older patients, and the lesions located in lower extremities were most common in younger ones.7

When metastatic, the presenting symptoms depend on the organ of involvement. The patient may present with a cough, dyspnoea, haemoptysis, jaundice, seizures, palpable subcutaneous masses.7

Identifying early melanomas WARD

The ABCDE criteria are a useful diagnostic tool for identifying early melanoma lesions. The characteristics of melanoma are commonly known by the acronym ABCDE.8

ABCDE criteria for melanoma detection asymmetry

Figure 1: ABCDE criteria for melanoma detection asymmetry8

  • A – Asymmetry
  • B - Irregular border
  • C - Colour variations, especially red, white, and blue tones in a brown or black lesion
  • D - Diameter greater than 6mm
  • E - Elevated surface.

Melanoma types

About 5%-12% of melanomas are hereditary. Hereditary melanomas tend to have different mutation profiles to non-hereditary melanomas. Two groups of metastatic melanomas can be distinguished: those harbouring a BRAFV600 mutation, which represents 40%-50% of all melanoma patients, and those harbouring other mutations.9,10

Melanoma has the highest rate of mutations of any cancer. In melanoma, BRAF mutation is most common in patients whose tumours arise on the skin without chronic sun-induced damage, whereas BRAF mutations are rare in melanomas arising from mucosal and acral sites.9,10

Among the BRAF mutations observed in melanoma, over 90% are at codon 600, and among these, over 90% are a single nucleotide mutation resulting in the substitution of glutamic acid for valine (BRAFV600E: nucleotide 1799 T >A, codon GTG > GAG).9,10

The second most common mutation is BRAFV600K substituting lysine for valine, which represents 5%-6% (GTG >AAG), followed by BRAFV600R (GTG >AGG), an infrequent two-nucleotide variation of the predominant mutation, BRAF V600 ′E2′ (GTG > GAA), and BRAF V600D (GTG > GAT).9,10

Treatment

The American Joint Committee on Cancer (AJCC) melanoma staging now distinguishes four sub-stages. In the early stages, melanoma can be treated successfully with surgery alone and survival rates are high. However, with increasing Breslow thickness (see box 1), the risk of being diagnosed with stage III disease increases. According to the AJCC, the five- and 10-year survival rates for melanoma stage IIIA to IIID is 93% and 88%.9

According to Funck-Brentano et al, treatment of patients with metastatic melanoma has considerably improved over the past decade – especially for patients with AJCC stage III (loco-regional metastases) or IV (distant metastases) totally resected melanoma.11

Historically, chemotherapy was the only treatment option available for patients with advanced melanoma. Dacarbazine was the first single chemotherapy agent approved for the treatment of metastatic melanoma and is routinely used in clinical practice.10

However, only between 5%-20% of patients responded to treatment, and a six-year OS rate was achieved in less than 2% of patients. In 2013 the American Food and Drug Administration (FDA) approved the first MEK inhibitor (trametinib) for the treatment of melanoma.10,15

In the adjuvant setting, two options are available to patients with BRAFV600-mutant AJCC stage III totally resected melanoma: anti-PD-1 blockers ( eg pembrolizumab) or BRAF plus MEK inhibitors (dabrafenib plus trametinib).10

The Dabrafenib With Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma (COMBI-AD) trial (2017) was the first prospective phase III trial to evaluate the BRAF and MEK inhibitors combination therapy as adjuvant treatment in patients with completely resected BRAF V600 mutation-positive stage III melanoma.11,12,13

The researchers randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150mg twice daily plus trametinib at a dose of 2mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary endpoint was relapse-free survival (RFS). Secondary endpoints included overall survival, distant metastasis-free survival (DMFS), freedom from relapse, and safety.11

At a median follow-up of 2.8 years, the estimated three-year rate of RFS was 58% in the combination therapy group and 39% in the placebo group. The three-year OS rate was 86% in the combination therapy group and 77% in the placebo group, but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019.9

Rates of DMFS and freedom from relapse were also higher in the combination therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma.11

Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects.11

On the basis of these results, the combination of dabrafenib plus trametinib has been approved by the FDA and the European Commission as adjuvant therapy for patients with completely resected BRAF V600E/K–mutant stage III melanoma.12

In 2018, Hauschild et al published an update on the COMBI-AD study which provided updated data on RFS and DMFS rates of patients in the study. Median patient follow-up was 44 months in the dabrafenib plus trametinib arm.12

RFS was also analysed by subgroups defined by baseline disease stage, nodal metastatic burden, and ulceration status. The fraction of patients who remained relapse-free long-term was estimated using a Weibull mixture cure-rate model.12

At a median follow-up of 44 months (dabrafenib plus trametinib) and 42 months (placebo), three- and four-year RFS rates were 59% in the dabrafenib plus trametinib arm and 40% and 38% in the placebo arm, respectively (hazard ratio [HR] 0.49).12

DMFS also favoured dabrafenib plus trametinib (HR 0.53). The estimated cure rate was 54% in the dabrafenib plus trametinib arm compared with 37% in the placebo arm.12

Subgroup analysis of RFS demonstrated similar treatment benefit regardless of baseline factors, including disease stage, nodal metastatic burden, and ulceration.12

Recently, Dummer et al (2020) evaluated the long-term (60 months) stability of the RFS in patients with resected stage III melanoma with BRAF V600E or V600K mutations, in the COMBI-AD study described previously.13

Patients received 12 months of oral dabrafenib (at a dose of 150mg twice daily) plus trametinib (2mg once daily) or two matched placebos. The primary endpoint was RFS. OS was not analysed, since the required number of events to trigger the final OS analysis had not been reached.13

The minimum duration of follow-up was 59 months (median patient follow-up, 60 months for dabrafenib plus trametinib and 58 months for placebo). At five years, the percentage of patients who were alive without relapse was 52% with dabrafenib plus trametinib and 36% with placebo.13

The percentage of patients who were alive without distant metastasis was 65% with dabrafenib plus trametinib and 54% with placebo. No clinically meaningful between-group difference in the incidence or severity of serious adverse events was reported during the follow-up period.13

Conclusion

With relapse-free survival rates of 52% at five years, the COMBI-AD phase III study proved that first-line, adjuvant treatment with dabrafenib plus trametinib provided durable benefits for patients with resected stage III melanoma with a BRAF V600E/K mutation.13

Box 1: Breslow’s depth of invasion (thickness)2

  • Tumours are classified into four categories based on the depth:
  • Less than or equal to 0.75mm
  • 0.76mm-1.5mm
  • 1.51mm-4mm
  • Greater than or equal to 4mm
  • References

    1. American Cancer Society. Key Statistics for Melanoma Skin Cancer. https://www.cancer.org/cancer/melanoma-skin-cancer/about/key-statistics.html

    2. Skin Cancer Foundation. Melanoma Overview. https://www.skincancer.org/skin-cancer-information/melanoma/

    3. Davis LE, Shalin SC and Tackett. Current state of melanoma diagnosis and treatment. Cancer Biology and Therapy, 2019.

    4. Matthews NH, Li W-Q, Qureshi AA et al. Chapter 1: Epidemiology of Melanoma. Cutaneous Melanoma: Etiology and Therapy [Internet], 2017.

    5. De Wet J, Steyn M, Jordaan HF et al. An Analysis of Biopsies for Suspected Skin Cancer at a Tertiary Care Dermatology Clinic in the Western Cape Province of South Africa. Journal of Skin Cancer, 2020.

    6. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin, 2017.

    7. Dominiques B, Lopes JM, Soares P and Populo H. Melanoma treatment in action. Immunotargets Ther, 2018.

    8. Stanienda-Sokol K, Salwoska N, Slawinska M et al. Primary Locations of Malignant Melanoma Lesions Depending on Patients’ Gender and Age. Asian Pac J Cancer Prev, 2017.

    9. Ascierto PA, Kirkwood JM and Grob J-J. The role of BRAF V600 mutation in melanoma. J Transl Med, 2012.

    10. Funck-Brentano E, Malissen N, Roger A, et al. Which adjuvant treatment for patients with BRAFV600-mutant cutaneous melanoma? Annales de Dermatologie et de Vénéréologie, 2021.

    11. Cheng Y and Tian H. Current Development Status of MEK Inhibitors. Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry, 2017.

    12. Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. NEJM, 2017.

    13. Hauschild A, Dummer R, Schadendorf D, et al. Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected BRAF V600–Mutant Stage III Melanoma. J Clin Oncol, 2018.

    14. Drummer R, Hauschild A, Santinami M, et al. Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. NEJM, 2020.

    15. Bhatia S, Tykodi SS, and Thompson JA. Treatment of Metastatic Melanoma: An Overview. Oncology, 2010.