Malignant melanoma of the skin is the skin tumor with the highest rate of metastasis and is associated with more than 90% of all deaths from skin tumors. More than 90% of melanomas occur as primary tumors of the skin (cutaneous melanomas), 5% are found primarily in the eye, often in the area of the retina (ocular melanomas), and in a few cases malignant melanomas are also found in the mucous membrane.
Melanoma is generally curable if diagnosed early. An essential requirement is a resection with sufficient safety margin. However, the early tendency to metastasize is problematic. The locoregional metastasis stage (AJCC 2017 stage IIIA, IIIB and IIIC) comprises a clinically and prognostically heterogeneous patient group. The 5-year survival rate is between 23% and 87%. The median survival time for patients with stage IV metastatic melanoma is estimated to be 8‑12 months with a large interindividual variation. The algorithm of drug treatment in stage IV and non-resectable stage III includes targeted molecular therapies or immunotherapy.
GENOMIC ALTERATIONS
Variants in BRAF are detected in 40% to 50% of cutaneous melanomas and lead to constitutive activation of the kinase function. The most common variant in BRAF (Val600Glu) accounts for 70% to 88% of all BRAF variants. Other changes in BRAF occur in about 5% of all melanomas, and fusions involving BRAF.
Activating variants in NRAS are found in 20% to 30% of melanomas and typically exclude a variant in BRAF and KIT. They are associated with an aggressive course and unfavorable prognosis and may possibly cause resistance in BRAF-altered melanoma under therapy.
About 2% to 5% of melanomas show a variant in KIT. They are concentrated in mucosal melanoma and acral lentiginous melanoma. In about 50% of the cases, a response to imatinib or nilotinib (off label use) is observed. This is an option for patients with KIT variants after unsuccessful immunotherapy with checkpoint inhibitors (ICI).
Variants in NF1 occur in 12% to 18% of melanomas and in 46% of BRAF/NRAS wild-type melanomas and are associated with a high risk of death and poor overall survival. Furthermore, a reduced response to BRAF inhibitors was observed. In patients with NF1-altered melanomas, pan-RAF or type 2 RAF inhibitors in combination with MEK inhibitors or PI3K/mTOR inhibitors should be considered. NF1 variants correlate with a high tumor mutation burden (TMB), so that ICI should be considered.
In about 10% of mucosal melanomas and about 90% of uveal melanomas, variants are found at amino acid position Gln209 in GNA11 or GNAQ. While GNA11 and GNAQ variants are associated with poor overall survival in mucosal melanoma, variants in GNA11 in uveal melanoma are associated with more aggressive behavior. CDKN2A variants are found in 2% of all melanomas and in 30% to 40% of familial melanomas.
Fusions involving the NTRK1, NTRK2 and NTRK3 genes are very rare in melanoma (<1%). However, they are associated with a high response rate to the TRK inhibitors larotrectinib and entrectinib.
POSSIBLE THERAPIES
Two BRAF inhibitors (vemurafenib and dabrafenib) have been approved by the FDA as standard therapy for advanced melanoma and show a response in approximately 50% of patients when used as monotherapy. Unfortunately, relapses often occur after completion of therapy due to acquired resistance to BRAF inhibitors. The combination of BRAF and MEK inhibitors (dabrafenib and trametinib or vemurafenib and combimetinib) appears to slow the development of resistance and shows prolonged progression-free and overall survival compared to BRAF inhibitor monotherapy. Melanomas with variants close to codon 600 (especially Leu597 and Lys601) also show a response to MEK inhibitors or to a combination of BRAF and MEK inhibitors. Fusions involving BRAF also show a response to MEK inhibitors and non-specific RAF inhibitors (e.g., sorafenib). An alternative is ICI, although no data are available on the best sequential therapy of BRAF/MEK inhibitors and checkpoint inhibitors.
For melanoma patients with non-resectable metastases, the option of ICI should be examined. PD-1 antibodies or their combination with ipilimumab are superior to monotherapy with ipilimumab in terms of progression-free survival. PD-L1 expression is not always a reliable marker for predicting therapy response, since PD-L1 negative tumors also respond and PD-L1 expression is inconsistent between primary tumor and metastases and between metastases in about 50% of cases; therefore, determining the TMB is supportive since TMB is significantly higher in patients with a good response to therapy than in patients with a poor response.
Despite promising early clinical data, only a few patients with NRAS-altered melanoma benefit from treatment with a MEK inhibitor. However, preliminary data show tumor regression as well as a response or stable disease with a combination of MEK inhibitors and CDK4/6 inhibitors in patients with metastatic NRAS-altered melanoma (off label use).
GENE PANEL
19 genes: BAP1, BRAF, BRCA2, CDK4, CDKN2A, GNA11, GNAQ, GNAS, HRAS, KIT, MAP2K1, MITF, NF1, NRAS, NTRK1, NTRK2, NTRK3, PTEN, TERT
TARGETED PANEL
BRAF, KIT, NRAS, NTRK1/2/3 fusion
